Author:
Bergonzo Christina,Henriksen Niel M.,Roe Daniel R.,Cheatham Thomas E.
Abstract
Recent modifications and improvements to standard nucleic acid force fields have attempted to fix problems and issues that have been observed as longer timescale simulations have become routine. Although previous work has shown the ability to fold the UUCG stem–loop structure, until now no group has attempted to quantify the performance of current force fields using highly converged structural populations of the tetraloop conformational ensemble. In this study, we report the use of multiple independent sets of multidimensional replica exchange molecular dynamics (M-REMD) simulations with different initial conditions to generate well-converged conformational ensembles for the tetranucleotides r(GACC) and r(CCCC), as well as the larger UUCG tetraloop motif. By generating what is to our knowledge the most complete RNA structure ensembles reported to date for these systems, we remove the coupling between force field errors and errors due to incomplete sampling, providing a comprehensive comparison between current top-performing MD force fields for RNA. Of the RNA force fields tested in this study, none demonstrate the ability to correctly identify the most thermodynamically stable structure for all three systems. We discuss the deficiencies present in each potential function and suggest areas where improvements can be made. The results imply that although “short” (nsec-μsec timescale) simulations may stay close to their respective experimental structures and may well reproduce experimental observables, inevitably the current force fields will populate alternative incorrect structures that are more stable than those observed via experiment.
Funder
National Institutes of Health
Blue Waters Sustained-Petascale Computing Project
Extreme Science and Engineering Discovery Environment
National Science Foundation
University of Utah
Publisher
Cold Spring Harbor Laboratory
Reference56 articles.
1. Performance of Molecular Mechanics Force Fields for RNA Simulations: Stability of UUCG and GNRA Hairpins
2. Molecular dynamics with coupling to an external bath
3. Multidimensional Replica Exchange Molecular Dynamics Yields a Converged Ensemble of an RNA Tetranucleotide
4. Structures, Kinetics, Thermodynamics, and Biological Functions of RNA Hairpins
5. Case DA , Darden TA , Cheatham TE III , Simmerling CL , Wang J , Duke RE , Luo R , Walker RC , Zhang W , Merz KM , 2012. AMBER 12. University of California, San Francisco, CA.
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