Constructing multi-resolution markov state models (MSMS) to elucidate RNA hairpin folding mechanisms

Xuhui Huang, Yuan Yao, Gregory R. Bowman, Jian Sun, Leonidas J. Guibas, Gunnar Carlsson, Vijay S. Pande

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

54 Scopus citations

Abstract

Simulating biologically relevant timescales at atomic resolution is a challenging task since typical atomistic simulations are at least two orders of magnitude shorter. Markov State Models (MSMs) provide one means of overcoming this gap without sacrificing atomic resolution by extracting long time dynamics from short simulations. MSMs coarse grain space by dividing conformational space into long-lived, or metastable, states. This is equivalent to coarse graining time by integrating out fast motions within metastable states. By varying the degree of coarse graining one can vary the resolution of an MSM; therefore, MSMs are inherently multi-resolution. Here we introduce a new algorithm Super-level-set Hierarchical Clustering (SHC), to our knowledge, the first algorithm focused on constructing MSMs at multiple resolutions. The key insight of this algorithm is to generate a set of super levels covering different density regions of phase space, then cluster each super level separately, and finally recombine this information into a single MSM. SHC is able to produce MSMs at different resolutions using different super density level sets. To demonstrate the power of this algorithm we apply it to a small RNA hairpin, generating MSMs at four different resolutions. We validate these MSMs by showing that they are able to reproduce the original simulation data. Furthermore, long time folding dynamics are extracted from these models. The results show that there are no metastable on-pathway intermediate states. Instead, the folded state serves as a hub directly connected to multiple unfolded/misfolded states which are separated from each other by large free energy barriers.

Original languageEnglish
Title of host publicationPacific Symposium on Biocomputing 2010, PSB 2010
Pages228-239
Number of pages12
StatePublished - 2010
Event15th Pacific Symposium on Biocomputing, PSB 2010 - Kamuela, HI, United States
Duration: Jan 4 2010Jan 8 2010

Publication series

NamePacific Symposium on Biocomputing 2010, PSB 2010

Conference

Conference15th Pacific Symposium on Biocomputing, PSB 2010
CountryUnited States
CityKamuela, HI
Period01/4/1001/8/10

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