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Discovering free energy basins for macromolecular systems via guided multiscale simulation.

Authors
  • Sereda, Yuriy V1
  • Singharoy, Abhishek B
  • Jarrold, Martin F
  • Ortoleva, Peter J
  • 1 Center for Cell and Virus Theory, Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, Indiana 47405, United States. , (India)
Type
Published Article
Journal
The Journal of Physical Chemistry B
Publisher
American Chemical Society
Publication Date
Jul 26, 2012
Volume
116
Issue
29
Pages
8534–8544
Identifiers
DOI: 10.1021/jp2126174
PMID: 22423635
Source
Medline
License
Unknown

Abstract

An approach for the automated discovery of low free energy states of macromolecular systems is presented. The method does not involve delineating the entire free energy landscape but proceeds in a sequential free energy minimizing state discovery; i.e., it first discovers one low free energy state and then automatically seeks a distinct neighboring one. These states and the associated ensembles of atomistic configurations are characterized by coarse-grained variables capturing the large-scale structure of the system. A key facet of our approach is the identification of such coarse-grained variables. Evolution of these variables is governed by Langevin dynamics driven by thermal-average forces and mediated by diffusivities, both of which are constructed by an ensemble of short molecular dynamics runs. In the present approach, the thermal-average forces are modified to account for the entropy changes following from our knowledge of the free energy basins already discovered. Such forces guide the system away from the known free energy minima, over free energy barriers, and to a new one. The theory is demonstrated for lactoferrin, known to have multiple energy-minimizing structures. The approach is validated using experimental structures and traditional molecular dynamics. The method can be generalized to enable the interpretation of nanocharacterization data (e.g., ion mobility-mass spectrometry, atomic force microscopy, chemical labeling, and nanopore measurements).

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