TY - JOUR
T1 - Molecular dynamics simulations of viral RNA polymerases link conserved and correlated motions of functional elements to fidelity
AU - Moustafa, Ibrahim M.
AU - Shen, Hujun
AU - Morton, Brandon
AU - Colina, Coray M.
AU - Cameron, Craig E.
N1 - Funding Information:
This study was funded by a grant from National Institutes of Health ( AI045818 to C.E.C.) and a seed grant from the Penn State Huck Institute of the Life Sciences and Material Research Institute (to C.M.C. and C.E.C.). This research was also supported in part by the National Science Foundation through TeraGrid resources provided by Pittsburgh Supercomputing Center (grant number MCB080068N to C.M.C.). We acknowledge the Information Technology Services-High Performance Computing group and the Materials Simulation Center at Penn State University for their computer resources and Dr. Ping Lin for the valuable time and help. We thank Jamie Arnold, Philip Bevilacqua, David Boehr, Janna Maranas, Scott Showalter and Eric Smidansky for comments on the manuscript.
PY - 2011/7/1
Y1 - 2011/7/1
N2 - The viral RNA-dependent RNA polymerase (RdRp) is essential for multiplication of all RNA viruses. The sequence diversity of an RNA virus population contributes to its ability to infect the host. This diversity emanates from errors made by the RdRp during RNA synthesis. The physical basis for RdRp fidelity is unclear but is linked to conformational changes occurring during the nucleotide-addition cycle. To understand RdRp dynamics that might influence RdRp function, we have analyzed all-atom molecular dynamics simulations on the nanosecond timescale of four RdRps from the picornavirus family that exhibit 30-74% sequence identity. Principal component analysis showed that the major motions observed during the simulations derived from conserved structural motifs and regions of known function. The dynamics of residues participating in the same biochemical property, for example, RNA binding, nucleotide binding or catalysis, were correlated even when spatially distant on the RdRp structure. The conserved and correlated dynamics of functional structural elements suggest coevolution of dynamics with structure and function of the RdRp. Crystal structures of all picornavirus RdRps exhibit a template-nascent RNA duplex channel too small to fully accommodate duplex RNA. Simulations revealed opening and closing motions of the RNA and nucleoside triphosphate channels, which might be relevant to nucleoside triphosphate entry, inorganic pyrophosphate exit and translocation. A role for nanosecond timescale dynamics in RdRp fidelity is supported by the altered dynamics of the high-fidelity G64S derivative of PV RdRp relative to wild-type enzyme.
AB - The viral RNA-dependent RNA polymerase (RdRp) is essential for multiplication of all RNA viruses. The sequence diversity of an RNA virus population contributes to its ability to infect the host. This diversity emanates from errors made by the RdRp during RNA synthesis. The physical basis for RdRp fidelity is unclear but is linked to conformational changes occurring during the nucleotide-addition cycle. To understand RdRp dynamics that might influence RdRp function, we have analyzed all-atom molecular dynamics simulations on the nanosecond timescale of four RdRps from the picornavirus family that exhibit 30-74% sequence identity. Principal component analysis showed that the major motions observed during the simulations derived from conserved structural motifs and regions of known function. The dynamics of residues participating in the same biochemical property, for example, RNA binding, nucleotide binding or catalysis, were correlated even when spatially distant on the RdRp structure. The conserved and correlated dynamics of functional structural elements suggest coevolution of dynamics with structure and function of the RdRp. Crystal structures of all picornavirus RdRps exhibit a template-nascent RNA duplex channel too small to fully accommodate duplex RNA. Simulations revealed opening and closing motions of the RNA and nucleoside triphosphate channels, which might be relevant to nucleoside triphosphate entry, inorganic pyrophosphate exit and translocation. A role for nanosecond timescale dynamics in RdRp fidelity is supported by the altered dynamics of the high-fidelity G64S derivative of PV RdRp relative to wild-type enzyme.
UR - http://www.scopus.com/inward/record.url?scp=79958744018&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79958744018&partnerID=8YFLogxK
U2 - 10.1016/j.jmb.2011.04.078
DO - 10.1016/j.jmb.2011.04.078
M3 - Article
C2 - 21575642
AN - SCOPUS:79958744018
SN - 0022-2836
VL - 410
SP - 159
EP - 181
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 1
ER -