caa a22 4500 467938954 CHVBK 20180406153006.0 cr unu---uuuuu 170328e20060501xx s 000 0 eng 10.1007/s10822-006-9049-z doi (NATIONALLICENCE)springer-10.1007/s10822-006-9049-z RNA unrestrained molecular dynamics ensemble improves agreement with experimental NMR data compared to single static structure: a test case [Elektronische Daten] [Robert Beckman, David Moreland, Shirley Louise-May, Christine Humblet] Nuclear magnetic resonance (NMR) provides structural and dynamic information reflecting an average, often non-linear, of multiple solution-state conformations. Therefore, a single optimized structure derived from NMR refinement may be misleading if the NMR data actually result from averaging of distinct conformers. It is hypothesized that a conformational ensemble generated by a valid molecular dynamics (MD) simulation should be able to improve agreement with the NMR data set compared with the single optimized starting structure. Using a model system consisting of two sequence-related self-complementary ribonucleotide octamers for which NMR data was available, 0.3ns particle mesh Ewald MD simulations were performed in the AMBER force field in the presence of explicit water and counterions. Agreement of the averaged properties of the molecular dynamics ensembles with NMR data such as homonuclear proton nuclear Overhauser effect (NOE)-based distance constraints, homonuclear proton and heteronuclear 1H-31P coupling constant (J) data, and qualitative NMR information on hydrogen bond occupancy, was systematically assessed. Despite the short length of the simulation, the ensemble generated from it agreed with the NMR experimental constraints more completely than the single optimized NMR structure. This suggests that short unrestrained MD simulations may be of utility in interpreting NMR results. As expected, a 0.5ns simulation utilizing a distance dependent dielectric did not improve agreement with the NMR data, consistent with its inferior exploration of conformational space as assessed by 2-D RMSD plots. Thus, ability to rapidly improve agreement with NMR constraints may be a sensitive diagnostic of the MD methods themselves. Springer Science+Business Media B.V., 2006 Molecular dynamics nationallicence Nuclear magnetic resonance nationallicence Particle mesh Ewald nationallicence Ribonucleic acid nationallicence Beckman Robert Discovery Research Informatics, Computer-Assisted Drug Design, Pfizer Global Research and Development, 48105, Ann Arbor, MI, USA aut Moreland David Discovery Research Informatics, Computer-Assisted Drug Design, Pfizer Global Research and Development, 48105, Ann Arbor, MI, USA aut Louise-May Shirley Discovery Research Informatics, Computer-Assisted Drug Design, Pfizer Global Research and Development, 48105, Ann Arbor, MI, USA aut Humblet Christine Discovery Research Informatics, Computer-Assisted Drug Design, Pfizer Global Research and Development, 48105, Ann Arbor, MI, USA aut Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/5(2006-05-01), 263-279 0920-654X 20:5<263 2006 20 10822 https://doi.org/10.1007/s10822-006-9049-z text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10822-006-9049-z text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Beckman Robert Discovery Research Informatics, Computer-Assisted Drug Design, Pfizer Global Research and Development, 48105, Ann Arbor, MI, USA aut NATIONALLICENCE 700 1- Moreland David Discovery Research Informatics, Computer-Assisted Drug Design, Pfizer Global Research and Development, 48105, Ann Arbor, MI, USA aut NATIONALLICENCE 700 1- Louise-May Shirley Discovery Research Informatics, Computer-Assisted Drug Design, Pfizer Global Research and Development, 48105, Ann Arbor, MI, USA aut NATIONALLICENCE 700 1- Humblet Christine Discovery Research Informatics, Computer-Assisted Drug Design, Pfizer Global Research and Development, 48105, Ann Arbor, MI, USA aut NATIONALLICENCE 773 0- Journal of Computer-Aided Molecular Design Kluwer Academic Publishers 20/5(2006-05-01), 263-279 0920-654X 20:5<263 2006 20 10822 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer