Abstract
BackgroundIn this study, we extended the replica exchange Monte Carlo (REMC) sampling method to protein–small molecule docking conformational prediction using RosettaLigand. In contrast to the traditional Monte Carlo (MC) and REMC sampling methods, these methods use multi-objective optimization Pareto front information to facilitate the selection of replicas for exchange.ResultsThe Pareto front information generated to select lower energy conformations as representative conformation structure replicas can facilitate the convergence of the available conformational space, including available near-native structures. Furthermore, our approach directly provides min-min scenario Pareto optimal solutions, as well as a hybrid of the min-min and max-min scenario Pareto optimal solutions with lower energy conformations for use as structure templates in the REMC sampling method. These methods were validated based on a thorough analysis of a benchmark data set containing 16 benchmark test cases. An in-depth comparison between MC, REMC, multi-objective optimization-REMC (MO-REMC), and hybrid MO-REMC (HMO-REMC) sampling methods was performed to illustrate the differences between the four conformational search strategies.ConclusionsOur findings demonstrate that the MO-REMC and HMO-REMC conformational sampling methods are powerful approaches for obtaining protein–small molecule docking conformational predictions based on the binding energy of complexes in RosettaLigand.
Highlights
In this study, we extended the replica exchange Monte Carlo (REMC) sampling method to protein–small molecule docking conformational prediction using RosettaLigand
The results showed that the interface delta (IFDelta) values could vary dramatically for different targets and sampling methods, whereas the IFDelta scores obtained for the same target with the REMC, multi-objective optimization-REMC (MO-REMC), and HMOREMC enhanced sampling methods varied only slightly
In this study, we developed REMC sampling methods based on multi-objective optimization for predicting conformations in protein–small ligand docking with RosettaLigand
Summary
We extended the replica exchange Monte Carlo (REMC) sampling method to protein–small molecule docking conformational prediction using RosettaLigand. Given the importance of conformational search, several software systems have been developed over the past 20 years, including Dock [3], FlexX [4, 5], GOLD [6, 7], Autodock [8,9,10], Glide [11] and others [12,13,14]. These software systems and sampling methods can efficiently predict realistic complex protein– ligand docking structures according to predefined sets of criteria [15]. In order to improve the sampling procedure, various advanced sampling approaches have been developed in recent years [18,19,20]
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