Efficient and accurate calculation of proline cis/trans isomerization free energies from Hamiltonian replica exchange molecular dynamics simulations

Maximilian Kienlein, Martin Zacharias, Maria M. Reif

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Proline cis/trans isomerization plays an important role in many biological processes but occurs on time scales not accessible to brute-force molecular dynamics (MD) simulations. We have designed a new Hamiltonian replica exchange scheme, ω-bias potential replica exchange molecular dynamics (ωBP-REMD), to efficiently and accurately calculate proline cis/trans isomerization free energies. ωBP-REMD is applied to various proline-containing tripeptides and a biologically important proline residue in the N2-domain of the gene-3-protein of phage fd in the wildtype and mutant variants of the protein. Excellent cis/trans transition rates are obtained. Reweighting of the sampled probability distribution along the peptide bond dihedral angle allows construction of the corresponding free-energy profile and calculation of the cis/trans isomerization free energy with high statistical precision. Very good agreement with experimental data is obtained. ωBP-REMD outperforms standard umbrella sampling in terms of convergence and agreement with experiment and strongly reduces perturbation of the local structure near the proline residue.

Original languageEnglish
Pages (from-to)1473-1484.e6
JournalStructure
Volume31
Issue number11
DOIs
StatePublished - 2 Nov 2023
Externally publishedYes

Keywords

  • conformational change
  • enhanced sampling
  • gene-3-protein of phage fd
  • isomerization free energy
  • molecular dynamics simulation
  • proline cis/trans isomerization

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