Reversible scaling of dihedral angle barriers during molecular dynamics to improve structure prediction of cyclic peptides

R. N. Riemann, M. Zacharias

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Peptide cyclization or chemical cross-linking has frequently been used to restrict the conformational freedom of a peptide, for example, to enhance its capacity for selective binding to a target receptor molecule. Structure prediction of cyclic peptides is important to evaluate possible conformations prior to synthesis. Because of the conformational constraints imposed by cyclization low energy conformations of cyclic peptides can be separated by large energy barriers. In order to improve the conformational search properties of molecular dynamics (MD) simulations a potential scaling method has been designed. The approach consists of several consecutive MD simulations with a specific lowering of dihedral energy barriers and reduced nonbonded interactions between atoms separated by three atoms followed by gradually scaling the potential until the original barriers are reached. Application to four cyclic penta- and hexapeptide test cases and a protein loop of known structure indicates that the potential scaling method is more efficient and faster in locating low energy conformations than standard MD simulations. Combined with a generalized Born implicit solvation model the low energy cyclic peptide conformations and the loop structure are in good agreement with experiment. Applications in the presence of explicit water molecules during the simulations showed also improved convergence to structures close to experiment compared with regular MD.

Original languageEnglish
Pages (from-to)354-364
Number of pages11
JournalJournal of Peptide Research
Volume63
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

Keywords

  • Conformational search
  • Drug design
  • Generalized Born model
  • Molecular modeling
  • Molecular simulation
  • Peptide design

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