pyDock: Electrostatics and desolvation for effective scoring of rigid‐body protein–protein docking

Abstract

The accurate scoring of rigid-body docking orientations represents one of the major difficulties in protein-protein docking prediction. Other challenges are the development of faster and more efficient sampling methods and the introduction of receptor and ligand flexibility during simulations. Overall, good discrimination of near-native docking poses from the very early stages of rigid-body protein docking is essential step before applying more costly interface refinement to the correct docking solutions. Here we explore a simple approach to scoring of rigid-body docking poses, which has been implemented in a program called pyDock. The scheme is based on Coulombic electrostatics with distance dependent dielectric constant, and implicit desolvation energy with atomic solvation parameters previously adjusted for rigid-body protein-protein docking. This scoring function is not highly dependent on specific geometry of the docking poses and therefore can be used in rigid-body docking sets generated by a variety of methods. We have tested the procedure in a large benchmark set of 80 unbound docking cases. The method is able to detect a near-native solution from 12,000 docking poses and place it within the 100 lowest-energy docking solutions in 56% of the cases, in a completely unrestricted manner and without any other additional information. More specifically, a near-native solution will lie within the top 20 solutions in 37% of the cases. The simplicity of the approach allows for a better understanding of the physical principles behind protein-protein association, and provides a fast tool for the evaluation of large sets of rigid-body docking poses in search of the near-native orientation.

Structural bases for the interaction and stabilization of the human amino acid transporter LAT2 with its ancillary protein 4F2hc

“…TEM, SPA, and 3D reconstruction were performed as described in SI Methods. Docking calculations of 4F2hc-ED-LAT2 interaction were performed based on the pyDock protocol (25), and the most relevant LAT2 residues for the interaction with 4F2hc were identified by using the NIP value (26). To validate the docking model, intersubunit crosslinking was performed in different versions of purified 4F2hc/LAT2 heterodimer expressed in HEK cells.…”

Elucidation of the MD-2/TLR4 Interface Required for Signaling by Lipid IVa

“…Low resolution docking is useful for determining the possible relative positions of the two proteins in the complex. High-resolution protein-protein docking was performed by the program pyDock (33). pyDock is a method for rigid-body protein-protein docking.…”

Integrative computational modeling of protein interactions

“…ZDOCK [27]), desolvation (e.g. pyDock [28]) or statistical potentials (PIPER [29], IRAD [30]). Other methods are less computationally efficient, but nevertheless powerful.…”

“…Electrostatic interactions are commonly included in scoring functions through a Coulomb potential, even in fast, exhaustive methods such as FFT-based Hex [26], ZDOCK [27] and pyDock [28]. Most methods also include an atomic repulsion term to avoid steric clashes, via implementation of molecular mechanics Lennard-Jones potentials (e.g.…”

“…Related to the buried surface area, several algorithms also incorporate a desolvation energy term that attempts to model the thermodynamic cost or gain associated with changes in the solvation layer of the individual molecules upon binding (e.g. FastContact [43], pyDock [28], HAD-DOCK [44], ZDOCK [45] and PatchDock [42]/FireDock [46]). Another common strategy in scoring is to use knowledge-based functions derived from statistical analysis of experimentally determined structures.…”