Efficient Ensemble Refinement by Reweighting.
J Chem Theory Comput
; 15(5): 3390-3401, 2019 May 14.
Article
in En
| MEDLINE
| ID: mdl-30939006
ABSTRACT
Ensemble refinement produces structural ensembles of flexible and dynamic biomolecules by integrating experimental data and molecular simulations. Here we present two efficient numerical methods to solve the computationally challenging maximum-entropy problem arising from a Bayesian formulation of ensemble refinement. Recasting the resulting constrained weight optimization problem into an unconstrained form enables the use of gradient-based algorithms. In two complementary formulations that differ in their dimensionality, we optimize either the log-weights directly or the generalized forces appearing in the explicit analytical form of the solution. We first demonstrate the robustness, accuracy, and efficiency of the two methods using synthetic data. We then use NMR J-couplings to reweight an all-atom molecular dynamics simulation ensemble of the disordered peptide Ala-5 simulated with the AMBER99SB*-ildn-q force field. After reweighting, we find a consistent increase in the population of the polyproline-II conformations and a decrease of α-helical-like conformations. Ensemble refinement makes it possible to infer detailed structural models for biomolecules exhibiting significant dynamics, such as intrinsically disordered proteins, by combining input from experiment and simulation in a balanced manner.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peptides
/
Algorithms
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Molecular Dynamics Simulation
Language:
En
Journal:
J Chem Theory Comput
Year:
2019
Document type:
Article
Affiliation country:
Germany
Publication country:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
/
USA