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Simulating oligomerization at experimental concentrations and long timescales: A Markov state model approach

J. Chem. Phys. 129, 214707 (2008); doi:10.1063/1.3010881

Published 4 December 2008

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Nicholas W. Kelley,1 V. Vishal,2 Grant A. Krafft,3 and Vijay S. Pande1,2
1Department of Biophysics, Stanford University, Stanford, California 94305, USA
2Departments of Chemistry, Stanford University, Stanford, California 94305, USA
3Acumen Pharmaceuticals, Inc., 385 Oyster Point Blvd., Suite 9A, South San Francisco, California 94080, USA
Here, we present a novel computational approach for describing the formation of oligomeric assemblies at experimental concentrations and timescales. We propose an extension to the Markovian state model approach, where one includes low concentration oligomeric states analytically. This allows simulation on long timescales (seconds timescale) and at arbitrarily low concentrations (e.g., the micromolar concentrations found in experiments), while still using an all-atom model for protein and solvent. As a proof of concept, we apply this methodology to the oligomerization of an Abeta peptide fragment (Abeta21–43). Abeta oligomers are now widely recognized as the primary neurotoxic structures leading to Alzheimer's disease. Our computational methods predict that Abeta trimers form at micromolar concentrations in 10  ms, while tetramers form 1000 times more slowly. Moreover, the simulation results predict specific intermonomer contacts present in the oligomer ensemble as well as putative structures for small molecular weight oligomers. Based on our simulations and statistical models, we propose a novel mutation to stabilize the trimeric form of Abeta in an experimentally verifiable manner. ©2008 American Institute of Physics
History: Received 28 March 2008; accepted 10 October 2008; published 4 December 2008
Permalink: http://link.aip.org/link/?JCPSA6/129/214707/1
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KEYWORDS and PACS

Keywords
PACS
  • 87.15.B-
    Structure of biomolecules
  • 87.15.R-
    Biochemical reactions and kinetics
  • 87.14.E-
    Proteins
  • 87.15.A-
    Theory, modeling and computer simulation in molecular biophysics
  • YEAR: 2008

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PUBLICATION DATA

ISSN:
0021-9606 (print)   1089-7690 (online)
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