Can We Execute Stable Microsecond-Scale Atomistic Simulations of Protein–RNA Complexes?

We report over 30 μs of unrestrained molecular dynamics simulations of six protein–RNA complexes in explicit solvent. We utilize the AMBER ff99bsc0χOL3 RNA force field combined with the ff99SB protein force field and its more recent ff12SB version with reparametrized side-chain dihedrals. The simula...

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Bibliographic Details
Published in:	Journal of chemical theory and computation Vol. 11; no. 3; pp. 1220 - 1243
Main Authors:	Krepl, M, Havrila, M, Stadlbauer, P, Banas, P, Otyepka, M, Pasulka, J, Stefl, R, Sponer, J
Format:	Journal Article
Language:	English
Published:	United States American Chemical Society 10-03-2015
Subjects:	Molecular Dynamics Simulation Proteins - chemistry RNA - chemistry Time Factors
Online Access:	Get full text
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Summary:	We report over 30 μs of unrestrained molecular dynamics simulations of six protein–RNA complexes in explicit solvent. We utilize the AMBER ff99bsc0χOL3 RNA force field combined with the ff99SB protein force field and its more recent ff12SB version with reparametrized side-chain dihedrals. The simulations show variable behavior, ranging from systems that are essentially stable to systems with progressive deviations from the experimental structure, which we could not stabilize anywhere close to the starting experimental structure. For some systems, microsecond-scale simulations are necessary to achieve stabilization after initial sizable structural perturbations. The results show that simulations of protein–RNA complexes are challenging and every system should be treated individually. The simulations are affected by numerous factors, including properties of the starting structures (the initially high force field potential energy, resolution limits, conformational averaging, crystal packing, etc.), force field imbalances, and real flexibility of the studied systems. These factors, and thus the simulation behavior, differ from system to system. The structural stability of simulated systems does not correlate with the size of buried interaction surface or experimentally determined binding affinities but reflects the type of protein–RNA recognition. Protein–RNA interfaces involving shape-specific recognition of RNA are more stable than those relying on sequence-specific RNA recognition. The differences between the protein force fields are considerably smaller than the uncertainties caused by sampling and starting structures. The ff12SB improves description of the tyrosine side-chain group, which eliminates some problems associated with tyrosine dynamics.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1549-9618 1549-9626
DOI:	10.1021/ct5008108