Krepl, Miroslav, Clery, Antoine, Blatter, Markus, Allain, Frederic H.T. and Sponer, Jiri (2016) Synergy between NMR measurements and MD simulations of protein/RNA complexes: Application to the RRMs, the most common RNA Recognition Motifs. Nucleic acids research, 44 (13). pp. 6452-6470. ISSN 1362-4962; 0305-1048

Abstract

RNA Recognition Motif (RRM) proteins represent an abundant and variable class of proteins playing key roles in RNA biology. We present a joint atomistic molecular dynamics (MD) and experimental study of two RRM-containing proteins bound with their single-stranded target RNAs, namely the Fox-1 and SRSF1 complexes. The simulations are used in conjunction with NMR spectroscopy to interpret and expand the available structural data. We accumulate more than 50 µs of simulations and show that the MD method is robust enough to reliably describe the structural dynamics of the RRM-RNA complexes. The simulations predict unanticipated specific participation of Arg142 at the protein-RNA interface of the SRFS1 complex, which is subsequently confirmed by NMR and ITC measurements with mutant protein. We also predict that several segments of the protein-RNA interface may involve competition between dynamical local substates rather than firmly formed interactions, which is indirectly consistent with the primary NMR data. We demonstrate that the simulations can reveal important information not obtainable from the NMR data alone, can be used to interpret the NMR atomistic models, and can provide qualified predictions. Finally, we propose a protocol for “MD-adapted structure ensemble” as a way to integrate the simulation predictions and expand upon the deposited NMR structures. Unbiased µs-scale atomistic MD could become a technique routinely complementing the NMR measurements of protein-RNA complexes

Item Type:	Article
Date Deposited:	20 Aug 2016 00:45
Last Modified:	20 Aug 2016 00:45
URI:	https://oak.novartis.com/id/eprint/28577