Journal Article

Accelerated flexible protein-ligand docking using Hamiltonian replica exchange with a repulsive biasing potential

Ostermeir, Katja, Zacharias, Martin

2017

Overview

A molecular dynamics replica exchange based method has been developed that allows rapid identification of putative ligand binding sites on the surface of biomolecules. The approach employs a set of ambiguity restraints in replica simulations between receptor and ligand that allow close contacts in the reference replica but promotes transient dissociation in higher replicas. This avoids long-lived trapping of the ligand or partner proteins at nonspecific, sticky, sites on the receptor molecule and results in accelerated exploration of the possible binding regions. In contrast to common docking methods that require knowledge of the binding site, exclude solvent and often keep parts of receptor and ligand rigid the approach allows for full flexibility of binding partners. Application to peptide-protein, protein-protein and a drug-receptor system indicate rapid sampling of near-native binding regions even in case of starting far away from the native binding site outperforming continuous MD simulations. An application on a DNA minor groove binding ligand in complex with DNA demonstrates that it can also be used in explicit solvent simulations.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Binding Sites / Biology and Life Sciences / Biomolecules / Coordination compounds / Deoxyribonucleic acid / Dissociation / DNA / Docking / Flexibility / Hamiltonian systems / Homeodomain Proteins - chemistry / Homeodomain Proteins - metabolism / Humans / Ligands / Methods / Molecular dynamics / Molecular Dynamics Simulation / Physical Sciences / Physics / Pliability / Protein Conformation / Protein structure / Protein-protein interactions / Proteins / Research and Analysis Methods / Simulation / Solvents / Solvents - chemistry