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.
Highlights
Molecular dynamics simulations of nucleic acids are important for understanding motions over multiple timescales, which may be inaccessible by experimental methods, and for helping to clarify obscure experimental results (Cheatham and Case 2013)
The goals of this study are to remove the obstacle of sampling from force field assessment by using multidimensional replica exchange molecular dynamics (M-REMD) to sample configurational space to a higher degree of convergence
We show highly converged structure ensembles for the UUCG tetraloop, as well as the r(CCCC) and r(GACC) tetranucleotides for a variety of force fields
Summary
Molecular dynamics simulations of nucleic acids are important for understanding motions over multiple timescales, which may be inaccessible by experimental methods, and for helping to clarify obscure experimental results (Cheatham and Case 2013). RNA performs many different active roles within cells, making it important to accurately model structure and dynamics over multiple timescales (Meister 2011). This means that the accuracy of the potential function, or force field, is of the utmost importance when performing simulations of these highly charged and highly flexible polymers. In REMD, several independent simulations are run at different temperatures or Hamiltonians (referred to as T-REMD and H-REMD, respectively), and exchanges are attempted between them at specific intervals (Hansmann 1997; Sugita and Okamoto 1999) During these simulations the lower temperature replicas benefit from access to structures sampled at higher temperatures, where enthalpic barriers are more crossed, and the aggregate sampling for the entire simulation is improved. REMD simulations can be used to explore additional conformational space
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