Prediction of protein–protein complexes using replica exchange with repulsive scaling

Till Siebenmorgen, Michael Engelhard, Martin Zacharias

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23 Scopus citations


The realistic prediction of protein–protein complex structures is import to ultimately model the interaction of all proteins in a cell and for the design of new protein–protein interactions. In principle, molecular dynamics (MD) simulations allow one to follow the association process under realistic conditions including full partner flexibility and surrounding solvent. However, due to the many local binding energy minima at the surface of protein partners, MD simulations are frequently trapped for long times in transient association states. We have designed a replica-exchange based scheme employing different levels of a repulsive biasing between partners in each replica simulation. The bias acts only on intermolecular interactions based on an increase in effective pairwise van der Waals radii (repulsive scaling (RS)-REMD) without affecting interactions within each protein or with the solvent. For a set of five protein test cases (out of six) the RS-REMD technique allowed the sampling of near-native complex structures even when starting from the opposide site with respect to the native binding site for one partner. Using the same start structures and same computational demand regular MD simulations sampled near native complex structures only for one case. The method showed also improved results for the refinement of docked structures in the vicinity of the native binding geometry compared to regular MD refinement.

Original languageEnglish
Pages (from-to)1436-1447
Number of pages12
JournalJournal of Computational Chemistry
Issue number15
StatePublished - 5 Jun 2020
Externally publishedYes


  • binding free energy
  • docking refinement
  • free energy simulation
  • implicit solvent modeling
  • molecular dynamics simulation


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