ReplicOpter: A replicate optimizer for flexible docking

Abstract

We present a computationally efficient method for flexible refinement of docking predictions that reflects observed motions within a protein's structural class. Using structural homologs, we derive deformation models that capture likely motions. The models or "replicates" typically align along a rigid core, with a handful of flexible loops, linkers and tails. A few replicates can generate a much larger number of conformers, by exchanging each flexible region independently of the others. In this way, 10 replicates of a protein having 6 flexible regions can be used to generate a million conformations of a molecule. While this has obvious advantages in terms of sampling, the cost of assessing energies at every conformer is prohibitive, particularly when both molecules are flexible. Our approach addresses this combinatorial explosion, using key assumptions to compress the sampling by many orders of magnitude. ReplicOpter can perform hierarchical clustering from a list of rigid docking predictions and find nearby structures to any promising cluster representatives. These predicted complexes can then be refined and rescored. ReplicOpter's scoring function includes a Lennard-Jones potential softened using the Anderson-Chandler-Weeks decomposition, a desolvation term derived from the Atomic Contact Energy function, Coulombic electrostatics, hydrogen bonding, and terms to model pi-pi and pi-cation interactions. ReplicOpter has performed well on several recent CAPRI systems. We are presently benchmarking ReplicOpter on the complete docking benchmark set to fully establish its utility in refining rigid docking predictions and identifying near-native solutions.