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Enhanced Sampling and Overfitting Analyses in Structural Refinement of Nucleic Acids into Electron Microscopy Maps
journal contribution
posted on 2013-04-11, 00:00 authored by Harish Vashisth, Georgios Skiniotis, Charles L. BrooksFlexible fitting computational algorithms
are often useful to interpret
low-resolution maps of many macromolecular complexes generated by
electron microscopy (EM) imaging. One such atomistic simulation technique
is molecular dynamics flexible fitting (MDFF), which has been widely
applied to generate structural models of large ribonucleoprotein assemblies
such as the ribosome. We have previously shown that MDFF simulations
of globular proteins are sensitive to the resolution of the target
EM map and the strength of restraints used to preserve the secondary
structure elements during fitting (Vashisth, H.; et al. Structure 2012, 20, 1453−1462). In
this work, we aim to systematically examine the quality of structural
models of various nucleic acids obtained via MDFF by varying the map
resolution and the strength of structural restraints. We also demonstrate
how an enhanced conformational sampling technique for proteins, temperature-accelerated
molecular dynamics (TAMD), can be combined with MDFF for the structural
refinement of nucleic acids in EM maps. Finally, we also demonstrate
application of TAMD-assisted MDFF (TAMDFF) on a RNA/protein complex
and suggest that TAMDFF is a viable strategy for enhanced conformational
fitting in target maps of ribonucleoprotein complexes.
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Keywords
ribonucleoprotein assembliesEnhanced Samplingmap resolutionOverfitting Analysestarget EM mapdynamictarget mapsatomistic simulation techniqueribonucleoprotein complexessampling techniqueelectron microscopystrengthTAMDTAMDFFElectron Microscopy MapsFlexibleEM mapsMDFF simulationsrestraintstructure elementsglobular proteinsNucleic AcidsRNAacidStructural Refinementmodel
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