Force field dependence of riboswitch dynamics

Methods in Enzymology
Christian A Hanke, Holger Gohlke

Abstract

Riboswitches are noncoding regulatory elements that control gene expression in response to the presence of metabolites, which bind to the aptamer domain. Metabolite binding appears to occur through a combination of conformational selection and induced fit mechanism. This demands to characterize the structural dynamics of the apo state of aptamer domains. In principle, molecular dynamics (MD) simulations can give insights at the atomistic level into the dynamics of the aptamer domain. However, it is unclear to what extent contemporary force fields can bias such insights. Here, we show that the Amber force field ff99 yields the best agreement with detailed experimental observations on differences in the structural dynamics of wild type and mutant aptamer domains of the guanine-sensing riboswitch (Gsw), including a pronounced influence of Mg2+. In contrast, applying ff99 with parmbsc0 and parmχOL modifications (denoted ff10) results in strongly damped motions and overly stable tertiary loop-loop interactions. These results are based on 58 MD simulations with an aggregate simulation time>11 μs, careful modeling of Mg2+ ions, and thorough statistical testing. Our results suggest that the moderate stabilization of the χ-anti region i...Continue Reading

Citations

Oct 12, 2017·Journal of Chemical Information and Modeling·Christian A Hanke, Holger Gohlke

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