Multiscale simulations of protein folding: application to formation of secondary structures

Abstract

A multiscale simulation method of protein folding is proposed, using atomic representation of protein and solvent, combing genetic algorithms to determine the key protein structures from a global view, with molecular dynamic simulations to reveal the local folding pathways, thus providing an integrated landscape of protein folding. The method is found to be superior to previously investigated global search algorithms or dynamic simulations alone. For secondary structure formation of a selected peptide, RN24, the structures and dynamics produced by this method agree well with corresponding experimental results. Three most populated conformations are observed, including hairpin, β-sheet and α-helix. The energetic barriers separating these three structures are comparable to the kinetic energy of the atoms of the peptide, implying that the transition between these states can be easily triggered by kinetic perturbations, mainly through electrostatic interactions between charged atoms. Transitions between α-helix and β-sheet should jump over at least two energy barriers and may stay in the energetic trap of hairpin. It is proposed that the structure of proteins should be jointly governed by thermodynamic and dynamic factors; free energy is not the exclusive dominant for stability of proteins.

Keywords:

• protein folding
• stability
• multiscale
• compromise
• mesoscale
• genetic algorithm
• molecular dynamics simulation

Acknowledgements

This work is supported by the Ministry of Finance under Grant ZDYZ2008-2, the National Natural Science Foundation of China under the Grants 20821092 and 21103195, and Chinese Academy of Sciences under the Grant KGCX2-YW-124.