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Random walk in orthogonal space to achieve efficient free-energy simulation of complex systems

Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20227-32. doi: 10.1073/pnas.0810631106. Epub 2008 Dec 15.

Abstract

In the past few decades, many ingenious efforts have been made in the development of free-energy simulation methods. Because complex systems often undergo nontrivial structural transition during state switching, achieving efficient free-energy calculation can be challenging. As identified earlier, the "Hamiltonian" lagging, which reveals the fact that necessary structural relaxation falls behind the order parameter move, has been a primary problem for generally low free-energy simulation efficiency. Here, we propose an algorithm by achieving a random walk in both the order parameter space and its generalized force space; thereby, the order parameter move and the required conformational relaxation can be efficiently synchronized. As demonstrated in both the alchemical transition and the conformational transition, a leapfrog improvement in free-energy simulation efficiency can be obtained; for instance, (i) it allows us to solve a notoriously challenging problem: accurately predicting the pK(a) value of a buried titratable residue, Asp-66, in the interior of the V66E staphylococcal nuclease mutant, and (ii) it allows us to gain superior efficiency over the metadynamics algorithm.

MeSH terms

  • Computer Simulation*
  • Diffusion
  • Hydrogen-Ion Concentration
  • Methods
  • Micrococcal Nuclease / chemistry
  • Micrococcal Nuclease / genetics
  • Models, Chemical*
  • Protein Conformation
  • Thermodynamics*

Substances

  • Micrococcal Nuclease