Rapid equilibrium sampling initiated from nonequilibrium data

Xuhui Huang, Gregory R. Bowman, Sergio Bacallado, Vijay S. Pande

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Simulating the conformational dynamics of biomolecules is extremely difficult due to the rugged nature of their free energy landscapes and multiple long-lived, or metastable, states. Generalized ensemble (GE) algorithms, which have become popular in recent years, attempt to facilitate crossing between states at low temperatures by inducing a random walk in temperature space. Enthalpic barriers may be crossed more easily at high temperatures; however, entropic barriers will become more significant. This poses a problem because the dominant barriers to conformational change are entropic for many biological systems, such as the short RNA hairpin studied here. We present a new efficient algorithm for conformational sampling, called the adaptive seeding method (ASM), which uses nonequilibrium GE simulations to identify the metastable states, and seeds short simulations at constant temperature from each of them to quantitatively determine their equilibrium populations. Thus, the ASM takes advantage of the broad sampling possible with GE algorithms but generally crosses entropic barriers more efficiently during the seeding simulations at low temperature. We show that only local equilibrium is necessary for ASM, so very short seeding simulations may be used. Moreover, the ASM may be used to recover equilibrium properties from existing datasets that failed to converge, and is well suited to running on modern computer clusters.

Original languageEnglish
Pages (from-to)19765-19769
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number47
DOIs
StatePublished - Nov 24 2009

Keywords

  • Generalized ensemble methods
  • Markov state models
  • Molecular dynamics simulations
  • RNA hairpin folding

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