Transition pathway and its free-energy profile: a protocol for protein folding simulations

Int J Mol Sci. 2013 Aug 2;14(8):16058-75. doi: 10.3390/ijms140816058.


We propose a protocol that provides a systematic definition of reaction coordinate and related free-energy profile as the function of temperature for the protein-folding simulation. First, using action-derived molecular dynamics (ADMD), we investigate the dynamic folding pathway model of a protein between a fixed extended conformation and a compact conformation. We choose the pathway model to be the reaction coordinate, and the folding and unfolding processes are characterized by the ADMD step index, in contrast to the common a priori reaction coordinate as used in conventional studies. Second, we calculate free-energy profile as the function of temperature, by employing the replica-exchange molecular dynamics (REMD) method. The current method provides efficient exploration of conformational space and proper characterization of protein folding/unfolding dynamics from/to an arbitrary extended conformation. We demonstrate that combination of the two simulation methods, ADMD and REMD, provides understanding on molecular conformational changes in proteins. The protocol is tested on a small protein, penta-peptide of met-enkephalin. For the neuropeptide met-enkephalin system, folded, extended, and intermediate sates are well-defined through the free-energy profile over the reaction coordinate. Results are consistent with those in the literature.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enkephalin, Methionine / analysis*
  • Enkephalin, Methionine / metabolism*
  • Models, Theoretical
  • Molecular Dynamics Simulation*
  • Protein Conformation
  • Protein Folding*


  • Enkephalin, Methionine