Bioinformatics-2016-Basu-i262-70

Finding correct protein–protein docking models
using ProQDock
Sankar Basu and Bjo¨ rn Wallner*
Division of Bioinformatics, Department of Physics, Chemistry and Biology, Linko¨ping University, Linko¨ping SE-581 83,
Sweden
*To whom correspondence should be addressed
Abstract
Motivation: Protein–protein interactions are a key in virtually all biological processes. For a de-
tailed understanding of the biological processes, the structure of the protein complex is essential.
Given the current experimental techniques for structure determination, the vast majority of all pro-
tein complexes will never be solved by experimental techniques. In lack of experimental data, com-
putational docking methods can be used to predict the structure of the protein complex. A common
strategy is to generate many alternative docking solutions (atomic models) and then use a scoring
function to select the best. The success of the computational docking technique is, to a large de-
gree, dependent on the ability of the scoring function to accurately rank and score the many alter-
native docking models.
Results: Here, we present ProQDock, a scoring function that predicts the absolute quality of dock-
ing model measured by a novel protein docking quality score (DockQ). ProQDock uses support vec-
tor machines trained to predict the quality of protein docking models using features that can be
calculated from the docking model itself. By combining different types of features describing both
the protein–protein interface and the overall physical chemistry, it was possible to improve the cor-
relation with DockQ from 0.25 for the best individual feature (electrostatic complementarity) to 0.49
for the ﬁnal version of ProQDock. ProQDock performed better than the state-of-the-art methods
ZRANK and ZRANK2 in terms of correlations, ranking and ﬁnding correct models on an independ-
ent test set. Finally, we also demonstrate that it is possible to combine ProQDock with ZRANK and
ZRANK2 to improve performance even further.
Availability and implementation: http://bioinfo.ifm.liu.se/ProQDock
Contact: bjornw@ifm.liu.se
Supplementary information: Supplementary data are available at Bioinformatics online.
1 Introduction
Protein–protein interactions are crucial in almost all biological proc-
esses. To understand the mechanism of protein–protein interaction,
the structure of the protein complex is essential. Despite massive ef-
forts in structure determination the majority of protein complexes
are not and will never be available in the PDB (Berman et al., 2000).
Thus, there is a great need for computational methods that are able
to build models of protein complexes using docking.
Constructing models of protein complexes is a fundamental chal-
lenge in structural biology and despite years of investigation is still
unsolved. The problem can be divided into sampling and scoring,
where sampling is the problem of generating realistic docking mod-
els, and scoring is the problem of identifying the correct docking
models among many incorrect ones. A number of different
approaches have been applied to this problem ranging from
composite scoring describing the physics (Dominguez et al., 2003;
Cheng et al., 2007; Lyskov and Gray, 2008; Pierce and Weng, 2007,
2008) to methods derived from the statistics of structural databases
(Geppert et al., 2010; Liu and Vakser, 2011; Pons et al., 2011),
methods based on interface composition and geometry (Chang
et al., 2008; Khashan et al., 2012; Mitra and Pal, 2010) or comple-
mentarity (Gabb et al., 1997; Lawrence and Colman, 1993; McCoy
et al., 1997) and methods based on machine learning (Bordner and
Gorin, 2007; Chae et al., 2010). The different approaches provide
different aspects of docking model quality and could potentially re-
sult in higher performance when combined together (Moal et al.,
2013).
The multitude of approaches applied to the scoring problem
highlights the difficulty in scoring protein docking models. At one
end there are features that serve as critical filters for complex
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Bioinformatics, 32, 2016, i262–i270
doi: 10.1093/bioinformatics/btw257
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formation, like shape complementarity (Lawrence and Colman,
1993) while on the other end, there could be features that might
largely vary even among good-quality models. It is, for instance,
fairly easy to generate completely incorrect docking models with
good shape complementarity, as the van der Waals interactions con-
tribute favorably to the scoring function used in sampling. Another
problem in scoring docking models in general occurs when the dock-
ing models have been generated using different force fields, which is
often the case, in particular in the scoring part of CAPRI (Lensink
and Wodak, 2014). In this case, an almost perfectly correct model
scoring well in one force field, might contain some small clashes in
some other force field. Of course, it might be possible to refine the
docking models and remove the clash. However, this is time-
consuming and it might be worthy only if the model is correct, and
as most docking models are incorrect it would be better if promising
cases could be quickly detected without the need for extensive calcu-
lations. For instance, the use of coarse-grained scoring function,
which are less sensitive to local errors than all-atom scoring func-
tions (Viswanath et al., 2013) is one such example. However, it is
likely that other features such as electrostatic balance at the inter-
face, solvation, amino acid composition at the interface, etc. are also
important to discriminate incorrect and correct docking models and
finding the right balance between features is a highly non-trivial
task.
In this study, we present the development of an algorithm,
ProQDock, that predicts the quality of docking models using struc-
tural information, scoring functions and the predicted features were
combined using a support vector machine (SVM). The method is
optimized on realistic docking models to predict the DockQ score
(Basu and Wallner, 2016), of the corresponding model. DockQ is a
score between 0 and 1, which is similar to IS-score (Gao and
Skolnick, 2011) in its design, but optimized to reproduce the CAPRI
classification (Lensink et al., 2007).
2 Methods
2.1 Training set
To train ProQDock, two benchmark sets of protein–protein docking
models were used, the ‘CAPRI’ set (Lensink and Wodak, 2014),
which contains 19 013 models from 15 targets submitted to the
CAPRI scoring experiment, and the ‘MOAL’ set (Moal et al., 2013)
containing 56 015 models for 118 targets from the docking
Benchmark 4.0 (Hwang et al., 2010) using SwarmDock (Torchala
et al., 2013) to generate the models (generously provided by authors
of Moal et al.). The targets T36 (PDB ID: 2W5F) and T38 (3FM8)
from the CAPRI set were discarded because they lacked at least a
single acceptable (or better) model, resulting in 17 777 models from
13 targets.
The constructions of the two benchmark sets are completely dif-
ferent: the CAPRI set is based on docking model submitted to
CAPRI, which contains predictions from many different methods,
while the MOAL set contains models generated with only one
method. In that respect, the CAPRI set is probably more realistic, as
it contains models made with a variety of methods. On the other
hand, the number of models and in particular the number of targets
are small in the CAPRI set. Thus, to achieve a larger and more bal-
anced set, the CAPRI set and MOAL set were combined into one
set, ’CnM’ (CAPRI and MOAL), to be used in training ProQDock
using cross-validation (see below). The combined data set contained
73 792 docking models from 131 targets and is available at http://
bioinfo.ifm.liu.se/ProQDock/.
2.2 Independent test set, BM5
Although, training of the machine learning algorithm was per-
formed using a cross-validation procedure, the efficacy of
ProQDock was independently tested on a dataset based on 55 new
docking targets added to the Benchmark 4.0 in its updated version,
Benchmark 5.0 (Vreven et al., 2015). In total, 25 985 docking mod-
els generated with SwarmDock (Torchala et al., 2013) for these 55
targets were again kindly provided by the authors of Vreven et al.
(2015).
2.3 Native structures test set
To test the ability of ProQDock on native structure and to suggest a
range of predicted values characteristic of native protein–protein
complexes. A set consisting of 1879 co-crystallized interacting na-
tive structures with resolution better than 2 A˚ , and no missing back-
bone atoms were assembled using the ‘Build Database’ option from
Dockground (Anishchenko et al., 2014).
2.4 Cross-validation test sets
Five-fold cross-validation was used for training and assessing per-
formance. To this end the training set targets were divided in five
parts (cross-validation test sets) with no homologous proteins be-
tween them, four were used for training while testing the remaining
one. This was performed for each of the five parts to get predictions
for the whole set. All homologous proteins were placed in the same
cross-validation test set, to ensure that the training and testing data
for the same round of cross-validation did not contain any homolo-
gous between them. Blastclust (Altschul et al., 1990) was used to
cluster homologous sequences from all complexes using a strict cri-
teria 20% sequence similarity over at least 50% sequence coverage
(-L 0.5 -S 20). Two complexes were considered homologous if at
least one of the partners was homologous and placed in the same
cluster. Finally, all clusters were grouped into five with approxi-
mately the same number of targets, with the total number of models
spanning from 13 058 to 15 227 and the ratio of acceptable (or bet-
ter) to incorrect models, spanning a range of 0.016 to 0.14. Neither
different groupings (5-fold) nor jack-knifing (leave-one-out) did af-
fect the performance (data not shown). A similar cross-validation
strategy was used in the related problem of binding affinity predic-
tions (Marillet et al., 2016) having similar number of high-level fea-
tures (11 compared to 13 in the current study) and similar number
of available native target complexes (144 compared to 131).
2.5 Target function
The target function should ideally reflect the true quality of a given
protein–protein docking model. The state-of-the-art quality measure
in docking, established by the CAPRI community, is to use three dis-
tinct though related measures, Fnat, LRMS and iRMS (Me´ndez
et al., 2003). Fnat is the fraction of native interfacial contacts pre-
served in the model, LRMS the root mean square deviation for the
smaller chain (ligand) after superposition of the larger chain (recep-
tor) and iRMS is the RMS deviation of the interfacial atoms. By
applying various ad hoc cutoffs on these three measures, protein–
protein docking models are classified as ‘incorrect’, ‘acceptable’,
’medium’ or ’high’ quality. To avoid this classification scheme, we
recently developed DockQ (Basu and Wallner, 2016), which com-
bines Fnat, LRMS and iRMS into a continuous score between [0,1],
reflecting no similarity (0) to perfect similarity (1). It was demon-
strated that the continuous DockQ score can almost completely re-
capitulate the CAPRI classification into incorrect, acceptable,
medium and high quality (94% average PPV at 90% Recall) using
ProQDock i263

the following cutoffs: incorrect <0.23, acceptable [0.23,0.49), me-
dium [0.49,0.8), high >0.8. Thus, DockQ is essentially a higher
resolution version of the already established state of the art in the
docking field and used as the target function to train ProQDock.
2.6 SVM Training
The Support Vector Regression module in the SVMlight
package
(Joachims, 2002) was used to train ProQDock using 5-fold cross-
validation with radial basis function (RBF) kernel. The trade-off be-
tween training error and margin, C, and the RBF c parameter were
optimized using a grid search in the ranges; C from 2À15
to 210,
and
c from 2À10
to 210
, in log2 steps, maximizing the cross-validated
Pearson’s correlation coefficient. The epsilon width of tube for re-
gression was kept at 0.1 (default). Because there were large imbal-
ances in the number of acceptable (positive example) and incorrect
(negative) models, the cost factor (-j flag) option of SVMlearn was set
to the ratio of ’incorrect-to-acceptable’ models, so that the training
errors on negative examples could be outweighed by errors on posi-
tive examples (Morik et al., 1999). Rosetta energy terms and CPM
were scaled between 0 and 1 to improve convergence using logistic
scaling: Scaled(E) ¼ 1/(1 þ exp(-k(E-E0)), where E0 is the midpoint
of the sigmoid and k the steepness of the sigmoid curve. E0 and k
were optimized by estimating the cumulative distribution function,
cdf(E), for a given training feature using the kernel smoothing func-
tion ksdensity in MATLAB. E0 was chosen as the midpoint of the
data, i.e. cdf(E0) ¼ 0.5, and k to cover at least 99% of the data, by
selecting the lowest k (largest coverage) that made the Scaled(E)
pass through the points (E1, 0.01) or (E2, 0.99) where cdf(E1) ¼
0.01 and cdf(E2) ¼ 0.99.
2.7 Training features
A number of different features that describe either some specific
structural properties of protein–protein interfaces or the overall pro-
tein structural integrity and quality were calculated and used for
training ProQDock. The features are described in detail below.
2.7.1 Shape complementarity
The complementary in shape of protein–protein interface is a neces-
sary condition for binding. Shape complementary (Sc) of a protein–
protein interface (Lawrence and Colman, 1993) was calculated
using the program Sc part of CCP4 package (Winn et al., 2011). Sc
is defined in a range from À1 to 1 corresponding to anti- and per-
fectly correlated surfaces, respectively.
2.7.2 Electrostatic complementarity
The electrostatic character of native protein–protein interfaces is
generally associated with anti-correlated surface electrostatic poten-
tials (McCoy et al., 1997), reflected in positive values of the term,
electrostatic complementarity (EC). First, the molecular surface
(Connolly, 1983) was generated individually for both the partner
molecules using the software EDTSurf (Xu and Zhang, 2009), with
the scale factor for the optimum fit of the molecule in a bounding
box set to 1.0. The protein–protein interface atoms were defined as
atoms having a net (non-zero) change in solvent accessible surface
area calculated for the bound and unbound state by NACCESS
(Hubbard and Thornton, 1993). Hydrogen atoms were geometric-
ally fitted by REDUCE (Word et al., 1999), partial charges and
atomic radii were assigned by the AMBER94 all-atom molecular-
mechanics force field (Cornell et al., 1995). DelPhi (Li et al., 2012)
was used to compute the electrostatic potential for each surface
point (buried on association) at the interface, iteratively solving the
linearized version of the Poisson-Boltzman equation. From the elec-
trostatic surface potentials generated at both interfaces, EC was cal-
culated precisely according to the original methodology (McCoy
et al., 1997), which was also used to probe electrostatic complemen-
tarity (Em) within protein interiors (Basu et al., 2012). The internal
dielectric within the interior and buried interfaces of proteins were
generally considered to be low (e ¼ 2), although, the more advanced
multi-dielectric Gaussian smoothening method (Li et al., 2013) was
also adapted in a trial calculation in all native structures (DB3).
Both methods (single and multi-dielectric) resulted in similar EC val-
ues (rmsd: 0.15, Pearsons Correlation: 0.94). Similar to Sc, EC is
defined from À1 to 1, and it approaches 1 with increasing matching
(anti-correlation) of surface electrostatic potential generated on the
same surface, owing to two complementary set of atoms, whereas a
negative EC reflects unbalanced electric fields at the interface.
2.7.3 Relative size of the interface (nBSA, Fintres)
Neither the shape (Sc) nor EC, described above, takes the size of the
interface into account. Native complexes have been found to exist
spanning a wide range from small (< 10 amino acids) to large inter-
faces (Basu et al., 2014b). Also, only a few atoms at the interface
can give rise to very high Sc (Lawrence and Colman, 1993) depend-
ing on how good their shapes correlate (e.g. 2FPE: 39 atoms, Sc:
0.83, 1D2Z: 14 atoms, Sc: 0.57). Thus, both Sc and EC should be
coupled with additional features measuring the size of the interface.
Following similar formulations to that of the ’Overlap’ parameter
(Banerjee et al., 2003) introduced for protein interiors, here, two
related yet independent measures were calculated to account for the
size of the interface: (i) the normalized buried surface area (nBSA),
which measures the fraction of exposed surface area buried upon as-
sociation, and (ii) the fraction of residues buried at the interface
(Fintres).
2.7.4 Joint conditional probability of Sc, EC given nBSA
The joint conditional probability of Sc and EC given the actual size
of the interface obtained from native protein-protein interactions
(PPI) complexes was added as a separate feature. A similar function
was shown to be successful in fold-recognition (Basu et al., 2012).
To this end, nBSA, Sc and EC were computed in a database contain-
ing 1879 native structures from DOCKGROUND (see Section 2).
Based on the distribution of nBSA, interfaces were classified as small
(nBSA 0.05), medium (0.05 < nBSA 0.10) and large
(nBSA > 0.10). Distributions of Sc and EC were divided into inter-
vals of 0.05 and their normalized frequencies calculated. For a given
complex, CPM is the joint conditional probability of finding its
interface within a certain range of Sc and EC given its size (nBSA),
i.e. CPM ¼ log(P(ScjnBSA) þ log(P(ECjnBSA)), where P(ScjnBSA)
and P(ECjnBSA) are the probabilities of finding an interface within
a certain range of Sc and EC values conditioned by its relative size,
nBSA. CPM was set to 0 if P(ScjnBSA) or P(ECjnBSA) was 0 to
avoid the log score being undefined.
2.7.5 Link density
To capture the density of atomic contacts at the interface, the link
density (Ld) measure was implemented (Basu et al., 2011). Ld is
defined as the ratio of the actual number of links at the interface to
the theoretical maximum number of links, where a link is pair of
interacting residues from two chains defined as having at least one
pair of heavy atoms within 6A˚ . If M and N residues are found to be
at the interface from chain A and B, respectively, then the maximum
number of links is M Â N.
i264 S.Basu and B.Wallner

2.7.6 Interface contact preference score
It is well known that particular inter-residue contacts are preferred
at protein interfaces (Lo Conte et al., 1999). To account for this
fact, a Contact Preference Score (CPscore) was derived by training a
SVM to predict DockQ using inter-residue contact information
alone. The training was performed using the 5-fold cross-validation
sets, as described above, but before the training of ProQDock. The
inter-residue contact information was encoded as the fraction of any
residue-residue contact, weighted by a contact preference weight
available in the literature (Glaser et al., 2001). All possible combin-
ations of amino acid pairs comprise 210 residue–residue contacts.
Inter-residue contacts were defined as any two side-chain heavy
atoms (CA for Glycine) within 10A˚ between the two molecules. This
cutoff was deliberately kept somewhat relaxed in consistency with
the measure iRMS (Me´ndez et al., 2003), to account for all possible
combination of residue pairs at the interface.
2.7.7 Accessibility score
The expected distribution of amino acid residues with respect to
burial was estimated by the accessibility score (rGb—residue Given
burial) as detailed in an earlier publication (Basu et al., 2014a). rGb
measures the propensity of a particular amino acid residue given a
specific solvent accessibility. First, the burial of solvent exposure for
individual residues were estimated by the ratio of ASA of the amino
acid X in the polypeptide chain to that of an identical residue
located in a Gly-X-Gly peptide fragment with a fully extended con-
formation. The hydrophobic burial profile for a given PPI model
was then compared with an equivalent native profile. The rGb val-
ues for native PPI complexes are in the range of 0.059 (60.022)
(Basu et al., 2014b), where values 2r below the mean (here 0.011)
correspond to partially unfolded structures with hydrophobic resi-
dues being completely exposed to the solvent (Basu et al., 2014a).
The consideration of rGb as an all-atom feature was also motivated
by recent studies, emphasizing the plausible role of the non-interact-
ing protein surface in modulating the binding affinity of potential
protein–protein interactions (Visscher et al., 2015), primarily owing
to solvation effect.
2.7.8 Protein model accuracy (ProQ2)
The overall structural quality of the whole complex, taken to be a
folded pseudo-unimolecule, was estimated by the protein quality
predictor ProQ2 (Uziela and Wallner, 2016) shown to be one of the
best protein quality predictors in CASP11 quality assessment cat-
egory (Kryshtafovych et al., 2015).
2.7.9 Rosetta energy terms (rTs, Isc, Erep, Etmr)
The structure integrity and quality of packing was assessed by scor-
ing each protein–protein docking model using Rosetta all-atom en-
ergy function with the ’talaris2013’ weight set (O’Meara et al.,
2015). Before scoring, the side chains of each protein–protein dock-
ing model were rebuild. Ideally, each model should have been sub-
jected to a full Rosetta relax or at least a short minimization to
relieve potential backbone clashes. However, it turned out that even
only side chain rebuild and minimization was too time-consuming
(>5 min per model in some cases), given that the aim of the current
study is to develop a tool that should be able to score thousands of
models.
The Rosetta total score (rTs), the interface energy (Isc), the van
der Waals repulsive term (Erep) and the total score minus the repul-
sive term (Etmr) were used. The reason to separate the repulsive term
was that even a small clash might give high contributions to the total
energy, obfuscating potential good energy terms. Because all terms
except Isc depend on the chain length (the probability of higher
number of interactions increases with chain length), before SVM
training all terms except Isc were normalized by the length of the
target complex. Isc was not normalized because stability in terms of
binding energy is not necessarily a function of the interface size, and
there might be instances where a small but stable interface could be
energetically more favorable than a larger (unstable) interface.
2.8 ZRANK and ZRANK2
The knowledge-based all atom energy terms ZRANK (Pierce and
Weng, 2007) and ZRANK2 (Pierce and Weng, 2008) were also
computed, primarily for comparing the SVM results, but also for
use in the hybrid method ProQDockQZ. Both ZRANK and
ZRANK2 include van der Waals, electrostatics (Coulomb, using dis-
tance dependent dielectric) and desolvation energy terms. In add-
ition, ZRANK2 includes the IFACE term, an interface statistical
potential (Mintseris et al., 2007). ZRANK was primarily designed
to re-rank initial docking predictions from ZDOCK, while
ZRANK2 was designed toward refinement of protein docking mod-
els, in conjunction with RosettaDock (Gray et al., 2003). Besides the
IFACE potential, the weight for the repulsive van der Waals is sig-
nificantly smaller for ZRANK, making it less sensitive to small
clashes compared with ZRANK2.
2.9 Evaluation Measures
Apart from calculating direct correlation (Pearson’s) between scor-
ing function and the quality measure (DockQ) used as target func-
tion, performance was also measured by Receiver Operating
Characteristic (ROC) curves and ability to correctly rank models.
2.9.1 ROC curves
Performance of classifying protein–protein docking models as ac-
ceptable or better according to the CAPRI classification was eval-
uated based on true-positive rate (TPR, also known as recall), and
false-positive rate (FPR)
TRP ¼ Recall ¼
TP
P
TP
¼
TP
TP þ FN
FRP ¼
FP
P
FP
¼
FP
FP þ TN
where TP is the number of protein–protein docking models with a
CAPRI classification acceptable or better correctly predicted as posi-
tive (true positives); FP is the number of misclassified negative cases
(false positive); TN is the number of correctly predicted negatives
(true negatives); FN is the number of misclassified positive cases
(false negative). For any prediction method, ROC curves (TPR
versus FPR) were constructed by sorting the prediction from good to
bad and calculate TP, FP, FN, TN for all possible cutoffs for positive
prediction. The area under the curve (AUC) was calculated using the
trapezoidal numerical integration function trapz in MATLAB.
2.9.2 Ranking ability
The ability to properly rank models was measured by counting the
number of correct models, defined as acceptable or better, ranked at
top 1; within top 5, top 10 and top 100 by any given method. This
measure is identical to the measure in a recent benchmark of scoring
metrics for docking (Moal et al., 2013).
ProQDock i265

3 Results and Discussion
The aim of this study was to develop a method, ProQDock, that is
capable of predicting the absolute quality of protein–protein
docking models. The main idea is to calculate high-level features
(Table 1) from each protein–protein docking model and use these
features to predict the correctness of the protein–protein docking
model as measured by the DockQ score (see Section 2).
3.1 Development of ProQDock
SVM training was performed using 5-fold cross-validation using dif-
ferent subsets of features in Table 1 to predict the DockQ score on
the combined CnM dataset and the performances were primarily
evaluated by their Pearson’s Correlation values (versus DockQ).
Best individual correlations were obtained for EC (0.24) and nBSA
(0.17) (Fig. 1). Features were then categorized into interface (Int1,
Int2) and all-atom (All1, All2) features according to their physico-
chemical description, finally leading into four groups—Int1: size
and packing of the interface {nBSA, Fintres, Sc, Ld}; Int2: electro-
statics, binding energy and composition of the interface {EC, CPM,
CPscore, ISc}; All1: solvation and overall quality of the whole com-
plex {rGb, ProQ2}; All2: the Rosetta all-atom energy terms {rTs,
Erep, Etmr}. Each group had better correlations than any of their
constituting features (Fig. 1). Merging the interface and the all atom
features, correlations were further improved to 0.35 for {Int1 þ Int2}
and 0.25 for {All1 þ All2}, respectively. Finally, combining all fea-
tures, it was possible to improve the performance to 0.49 for
ProQDock (Fig. 1). The correlations indicate that the interface fea-
tures are more influential though the all atom features are also ne-
cessary to improve the overall performance.
In addition, ProQDock was combined with the external energy
terms, ZRANK (Pierce and Weng, 2007) and ZRANK2 (Pierce and
Weng, 2008) (ProQDockZ), using a linear weighted sum optimized
on the CnM set. ZRANK2 and ZRANK were chosen primarily as
independent methods to benchmark the performance of ProQDock
because ZRANK2 was one of the best methods in a recent bench-
mark of docking scoring functions (Moal et al., 2013). To analyze if
combining different complementary scoring functions would yield
better performance, the hybrid method, ProQDockZ, was also
included in the benchmark as a comparison. Indeed, the combined
method further improved the correlation slightly from 0.49 for
ProQDock to 0.50 for ProQDockZ (Fig. 1 and Table 2).
3.2 Benchmark on cross-validated data
The performances of ProQDock and ProQDockZ were compared
with ZRANK and ZRANK2 on the CnM set by analyzing correl-
ations (Table 2) as well as the ranking ability of each method and
ROC curves (Fig. 2). Out of 131 targets, ProQDockZ, ProQDock,
ZRANK2 and ZRANK could detect a correct (acceptable or better)
model in 36, 33, 32 and 23 cases at the top rank, respectively, while,
in 65, 61, 60 and 40 cases, at least one correct model was detected
within top 10 ranks. Thus, the ranking ability are similar for
ProQDock and ZRANK2, whereas the combined method
ProQDockZ is slightly better than both methods (Fig. 2A). A
more detailed analysis using ROC curves revealed that ProQDock
(AUC ¼ 0.87) in fact performed significantly better than both
ZRANK (AUC ¼ 0.71) and ZRANK2 (AUC ¼ 0.75). By using a
ProQDock score of 0.23 for correct predictions, ProQDock is able
to find 80% of the correct models (TPR ¼ 0.8 in Fig. 2B) at 20%
FPR. The combined method, ProQDockZ, further enhanced the
overall prediction ability (AUC ¼ 0.88), finding slightly more true
positives for all FPRs (Fig. 2B).
Both ProQDock and ProQDockZ correlate significantly better
than ZRANK and ZRANK2 with the true quality measure DockQ
(Table 2). ProQDockZ has a small but significantly better correl-
ation than ProQDock. ZRANK has a better correlation than
ZRANK2 despite the fact that ZRANK2 has been reported to have
the better performance (Moal et al., 2013). To explain the reason
for this, correlations were calculated separately for the CAPRI and
MOAL part of the CnM set (Table 2). This shows that ZRANK2
has a better correlation than ZRANK on MOAL but worse on
CAPRI. This is because the CAPRI set contains docking models cre-
ated using different methods, where many of the models have not
been energy minimized and hence will contain more clashes, as op-
posed to the models in the MOAL set, where all models were energy
Table 1. Description of ProQDock training features
Features Feature description
nBSA Normalized buried surface area
Fintres Fraction of residues at the interface
rGb Accessibility score
CPscore Contact Preference score
Ld Link Density at the interface
Sc Shape Complementarity at the interface
EC Electrostatic Complementarity at the interface
CPM Joint Conditional Probability of Sc, EC given nBSA
ProQ2 Protein model quality prediction
ISca
Rosetta interface energy
rTsa
Rosetta total energy
Erepa
Rosetta repulsive term
Etmra
Rosetta total energy minus repulsive
a
Energy terms, lower scores are better.
Fig. 1. Correlations with DockQ for different training features and their
combinations
Table 2. Correlations with DockQ on different datasets
Methods CnM
n ¼ 73 792
CAPRI
n ¼ 17 777
MOAL
n ¼ 56 015
BM5
n ¼ 25 985
ProQDock 0.49 60.01 0.55 60.01 0.34 60.01 0.37 60.01
ProQDockZ 0.50 60.01 0.57 60.01 0.36 60.01 0.38 60.01
ZRANK À0.31 60.01 À0.39 60.02 À0.21 60.01 À0.22 60.02
ZRANK2 À0.20 60.01 À0.25 60.02 À0.31 60.01 À0.33 60.01
Conﬁdence intervals are at 99% level.

minimized using SwarmDock (Torchala et al., 2013) (see Erep term
for MOAL and CAPRI in Supplementary Figs S1 and S2). A major
difference between ZRANK and ZRANK2 is that ZRANK2 has a
harder repulsive term, which makes it more sensitive for models
without clashes but obviously less sensitive on models with clashes.
ROC curves for CAPRI and MOAL also illustrate this behavior
(Fig. 3). ZRANK is better than ZRANK2 on CAPRI and vice versa on
MOAL, while ProQDock performs much better than both on CAPRI;
similar to ZRANK2 and much better than ZRANK on MOAL.
Demonstrating that ProQDock can capture both coarse-grained and
full-atom detail needed to perform well on both sets. As shown on
the combined set, CnM, ProQDockZ is marginally better than both
ProQDock and ZRANK2 on both subsets. The P-values correspond-
ing to the difference in correlations (versus DockQ) between both
ProQDock and ProQDockZ are < 0.01 over both ZRANK and
ZRANK2, suggesting that the correlations are significantly better at
99% confidence level implying definite improvement in perform-
ance (Table 2). This is true for both, the cross-validated (CnM) and
the independent benchmark (BM5).
3.3 Performance on independent test set BM5
The performance of the different scoring functions was further
tested on the independent dataset, BM5, consisting of 25 985 mod-
els from 55 targets. In ranking, ProQDock and ProQDockZ could
detect a correct (acceptable or better) model in 8 and 8 targets at the
top rank, respectively; while, ZRANK and ZRANK2 could detect 4
and 10 (Fig. 4A). Looking at the top 10 rank, ZRANK2 has a cor-
rect model for 16 targets, ZRANK has 17, ProQDock has 20 and
ProQDockZ have 23. Thus, in terms of ranking, ProQDock is better
than ZRANK and ZRANK2, and their (hybrid) combination,
ProQDockZ, is slightly better than both. This is also reflected in the
correlation values against DockQ where a slight increase was
observed from ProQDock (0.37) to ProQDockZ (0.38), while both
ZRANK2 (À0.33) and ZRANK (À0.22) obtained lower correlations
(Table 2). AUC values of the TPR versus FPR plots also follow the
same overall trends, with gradual improvements observed from
ZRANK (0.75), ZRANK2 (0.80) to ProQDock (0.82) and the hy-
brid method ProQDockZ (0.84). Thus, the cross-validated perform-
ance observed above is maintained on an independent benchmark
set.
3.4 Test on native structure
Obviously, ProQDock was designed to predict the quality of protein
docking models. However, it is also interesting to investigate
how they perform on native structures, like a reality check. To this
end, ProQDock was calculated for a set of high-resolution native
structures in the database DB3 (see Section 2). Indeed, the ProQDock
scores for native structures are much higher than the scores
obtained for the docking models (with the exception of ’High’ quality
models) from CnM included as reference (Fig. 5). The median
ProQDock for native structures is 0.64 compared with 0.11,
0.31, 0.44 and 0.68 for incorrect, acceptable, medium and high
docking model quality, respectively. The high-quality docking
models have scores similar to the score for native structures, which
makes sense because high-quality models are close to the native
structure.
3.5 Complementary of ProQDock and ZRANK2 in
ranking correct models
To analyze what features were characteristic to the complementarity
behavior of ProQDock and ZRANK2, which resulted in slight but
still improved prediction ability of the combined method
ProQDockZ, a statistical analysis of features for correct docking
Fig. 2. CnM performance measured by (A) the ability to rank a model with
quality acceptable or better among top 1, 5, 10 and 100 and (B) ROC curves;
the AUC values are given in the legend
Fig. 3. ROC curves for the (A) CAPRI part and (B) MOAL part of the CnM set.
AUC values in the legend
Fig. 4. BM5 performance measured by (A) the ability to rank a model with
quality acceptable or better among top 1, 5, 10 and 100 and (B) ROC curves;
the AUC values are given in the legend
Fig. 5. ProQDock score for native structure and incorrect, acceptable, medium
and high-quality models from the CnM set
ProQDock i267

models ranked high by ProQDock and not by ZRANK2 (set1) and
vice versa (set2) was performed. The sets were constructed by
considering the correct models in the MOAL set, up to the point
(Fig. 3B) where ProQDock and ZRANK2 intersects corresponding
to TPR of 70%, ensuring equal number top correct models before
applying the criteria above. ZRANK2 has a fairly strict van der
Waals repulsive term and will not be able to rank models with
clashes, so the MOAL set was chosen over CnM, as these models
have fewer clashes.
Statistics for individual features were calculated as mean and
standard deviation of the mean (standard error) for three sets con-
structed above (Table 3) and feature distributions for correct and in-
correct models were calculated (Supplementary Fig. S1). From the
statistics, two groups of features can be distinguished based on the
set of models selected by ProQDock and ZRANK2, one group (i)
with features that are significantly different both in Table 3 as well
as from the overall distributions of features of correct models
(Supplementary Fig. S1), i.e. a feature has to be significantly differ-
ent in Table 3 and significantly different from the mean of the over-
all distribution of correct models, and another group (ii) where
features that are invariant.
The features for which ProQDock and ZRANK2 select models
with significantly different ranges of values are (log10(Pval)<-3): nBSA,
Fintres, EC, ProQ, Isc, CPM, Ld and CPscore (Table 3). In all cases, ex-
cept for Ld, at least one of the values is also significantly different from
the mean of distribution of correct models (Supplementary Fig. S1, P
values not shown). Thus, features in group (i) are EC (0.26 for
ProQDock versus 0.01 for ZRANK2), Isc (0.27 versus 0.52, raw un-
scaled energy term corresponding to À11.6 versus À8.0 in Rosetta
Energy Units), CPscore (0.36 versus 0.22), Fintres (0.162 versus 0.239),
nBSA (0.047 versus 0.060, note that the scale for nBSA goes from 0 to
0.1), CPM (0.79 versus 0.71) and ProQ2 (0.84 versus 0.80). A common
trait to all features in this group (i) is that they all (with the exception of
ProQ2) describe the protein–protein interface. nBSA and Fintres meas-
ures the relative size of the interface using buried surface area and con-
tacts, respectively; EC describes the electrostatic complementarity of the
interface, Isc is the interface energy term in Rosetta, CPscore is an
SVM-based measure capturing the composition and contact preferences
of different amino acid residues at the interface, and CPM is a compos-
ite function of EC, Sc and nBSA (see Section 2). Although, ZRANK2 in-
cludes the IFACE potential (which is similar to CPscore) that describe
the interface, it is not nearly as detailed as the set of all features listed
above. Furthermore, ZRANK2 does not contain an advanced electro-
static term like EC, modeled on fine-grid Poisson–Boltzman continuum
electrostatics, which is advantageous over explicit electrostatic models
for intrinsically providing equilibrium solutions (Li et al., 2013). This is
most likely the reason why many correct models are missed by
ZRANK2. On the other hand, it is also possible that ProQDock focus
too much on interface features and EC in particular, so it misses many
of the correct models with low EC (Supplementary Fig. S1) that
ZRANK2 is able to pick up. In fact, a large fraction (21%) of correct
models have EC< 0, meaning that they have correlated surface electro-
static potentials (or in other words, unbalanced electric fields) at their
interface most likely compensated by stronger constraints of shape com-
plementarity. This is also true for native PPI models (from DB3) where
a similar fraction ($20%) of interfaces had a negative EC, suggesting
that EC has much more relaxed thresholds to satisfy compared with Sc
(packing), which is a more well-established necessary condition for
oligomer formation (Tsuchiya et al., 2006).
The second group (ii) with features that are similar in values at-
tained by models selected by both ProQDock and ZRANK2 (Table
3) are physico-chemical features: rGb, Sc, Erep, rTs, Etmr; all of
which have their equivalent representative terms in ZRANK2: rGb
is a solvation term, Sc is to some extent captured by the van der
Waal’s attractive term, Erep is the van der Waal’s repulsive term,
rTs is the total all-atom Rosetta energy (including Erep), Etmr is the
rTs excluding the Erep term. Thus, it makes sense that they are not
different between the correct models selected by ProQDock or
ZRANK2. However, the fact that they are invariant (or stable) sug-
gests that they provide a necessary but not sufficient condition for
correct (native like) interaction between two proteins. Hence, they
should be treated more as filters, which need to be satisfied. On the
other hand, the discriminative (variable) features in group (i) meas-
ure specific structural attributes that differ between different sets of
correct protein–protein docking models. Finally, it is noteworthy
that the overall docking model quality, DockQ, is in fact also mark-
edly better (P < 10 À 8
) for models selected only by ProQDock
(0.548 6 0.013) than those selected only by ZRANK2 (0.456 6
0.010). This is consistent with the observed trends in the discrimi-
nating features in both sets.
3.6 A case study of contrasting interface properties by
models ranked by ProQDock and ZRANK2
The complementary behavior of ProQDock and ZRANK2 in rank-
ing correct models is further illustrated by two models with contrast-
ing interface properties belonging to the two sets, the first is model
a7d from target 1K4C, ranked by ProQDock and not by ZRANK2,
and the second is model a1b from target 4CPA, ranked by ZRANK2
and not by ProQDock. Both models were ranked by the combined
method ProQDockZ. The models have almost identical overall
structural qualities with DockQ score of 0.59 and 0.55, respectively,
medium quality according to CAPRI classification. However, they
have vastly different values for several features, in particular at the
interface. EC, for instance, is completely different (0.76 for ranked
by ProQDock versus À0.69 for ranked by ZRANK2) illustrated by
the electric fields induced by the different chains on the surfaces
(Fig. 6). Also, the Rosetta interface score, Isc, is far better for the
model ranked by ProQDock (À21.2 and À4.5 Rosetta Energy
Table 3. Feature statistics for highly ranked correct models
Features ProQDock (set1)
247 models
50 targets
ZRANK2 (set2)
240 models
39 targets
log10 (Pval)
rGb 0.031 (60.001) 0.031 (60.002) À0.3
nBSA 0.047 (60.001) 0.060 (60.001) À23.3
Fintres 0.162 (60.004) 0.239 (60.006) À26.1
Sc 0.648 (60.004) 0.645 (60.004) À0.5
EC 0.264 (60.014) 0.012 (60.016) À28.8
ProQ2 0.836 (60.004) 0.799 (60.006) À6.5
Isc 0.270 (60.019) 0.520 (60.016) À21.4
rTs 0.469 (60.011) 0.459 (60.012) À0.6
Erep 0.491 (60.007) 0.515 (60.004) À2.6
Etmr 0.495 (60.009) 0.464 (60.011) À1.9
CPM 0.787 (60.008) 0.705 (60.010) À9.8
Ld 0.110 (60.003) 0.126 (60.002) À4.7
CPscore 0.359 (60.018) 0.224 (60.009) À10.4
DockQ 0.548 (60.013) 0.456 (60.010) À8.1
Descriptive statistics, mean and standard errors of features for set1: correct
models ranked by ProQDock and not by ZRANK2; set2: correct models
ranked by ZRANK2 and not by ProQDock; from the MOAL set. P-values are
calculated using t-test for the difference in mean between set1 and set2.
Features in bold are the set of features for which ProQDock and ZRANK2
have signiﬁcantly different values as deﬁned in group (i) in the text.

Units), which can partly but not fully be explained by the slightly
larger interface (56 versus 42 residues) in the two models. In con-
trast, CPscore is better for the model ranked by ZRANK2 (0.32
versus 0.44) possibly because of the similarity with IFACE term in
ZRANK2. Finally, Ld is much higher in the model ranked by
ZRANK2 (0.10 versus 0.15) (Note, the Ld distribution is narrow,
see Supplementary Fig. S1), revealing that the interface is more con-
nected for the latter (ranked by ZRANK2). However, both models
have good shape complementarity at the interface (0.68 in both
cases), which, as discussed earlier, is a more necessary condition for
inter-protein association, than the electrostatic balance at their
interface.
This example highlights the difficulty in scoring protein docking
models. At one end there are features that serve as critical filters for
complex formation, like shape complementarity. On the other hand,
there are variations with regard to features like EC, which probably
describes the diverse plethora of biological interactions.
4 Conclusions
The aim of this study was to develop a method that could improve the
detection of correct docking models in a set of many incorrect dock-
ing models. This was done by training SVMs to predict the quality of
protein docking models as measured by DockQ using features that
can be calculated from the docking model itself. By combining differ-
ent types of features describing both the protein–protein interface and
the overall physical chemistry, it was possible to improve the correl-
ation to DockQ from 0.25 for the best individual features to 0.49.
The final version of ProQDock performed better than the state-of-the-
art methods ZRANK and ZRANK2 in terms of correlations, ranking
and finding correct models on independent test set. Finally, we also
demonstrate that it is possible to combine ProQDock with ZRANK
and ZRANK2 to improve the overall performance even further. In
fact, based on the results described in Sections 3.5 and 3.6, the hybrid
method, ProQDockZ should be considered as a better choice over
both ProQDock and ZRANK to cover the diverse repertoire of plaus-
ible correct protein–protein docking models.
Funding
This work was supported by grants from the Swedish Research Council and
Swedish e-Science Research Center.
Conflict of Interest: none declared.
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