Protein-ligand docking using Hamiltonian replica exchange simulations with soft core potentials

Manuel P. Luitz, Martin Zacharias

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


Molecular dynamics (MD) simulations in explicit solvent allow studying receptor-ligand binding processes including full flexibility of the binding partners and an explicit inclusion of solvation effects. However, in MD simulations, the search for an optimal ligand-receptor complex geometry is frequently trapped in locally stable non-native binding geometries. A Hamiltonian replica-exchange (H-REMD)-based protocol has been designed to enhance the sampling of putative ligand-receptor complexes. It is based on softening nonbonded ligand-receptor interactions along the replicas and one reference replica under the control of the original force field. The efficiency of the method has been evaluated on two receptor-ligand systems and one protein-peptide complex. Starting from misplaced initial docking geometries, the H-REMD method reached in each case the known binding geometry significantly faster than a standard MD simulation. The approach could also be useful to identify and evaluate alternative binding geometries in a given binding region with small relative differences in binding free energy.

Original languageEnglish
Pages (from-to)1669-1675
Number of pages7
JournalJournal of Chemical Information and Modeling
Issue number6
StatePublished - 23 Jun 2014
Externally publishedYes


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