Comparison of Metrics of Inter-Structure Distance When Applied to Molecular Dynamics Simulations of Intrinsically Disordered Proteins

Abstract

Intrinsically disordered proteins (IDPs) exist in a naturally unfolded state consisting of a vast ensemble of transient conformations. Molecular dynamics (MD) simulations of IDPs are capable of estimating subsets of these ensembles, but most current tools to analyze MD trajectories are optimized to study protein simulations sampling relatively small conformational spaces. The commonly used measurement, root-mean-square deviation (RMSD), appears to saturate to maximal distance within tens to hundreds of nanoseconds in simulations of highly disordered proteins. Furthermore, in paired structures with inter-structure distances near the saturation of the RMSD measurement, the fits to the reference structures were sometimes meaningless. We have created and validated several tools based on the libraries and interface of the MD simulation software Gromacs 4 [Hess, et al. 2008]. In addition, we have completed a library which implements ten metrics of inter-structure distance. The metrics that we have investigated include modifications to the RMSD metric, various comparisons of backbone angles and dihedrals, calculations of correlation coefficients based on coordinates and shape, and two additional metrics of structure comparisons based on recent publications: MAMMOTH [Ortiz, et al. 2002] and elastic shape analysis [Liu, et al. 2011]. We will present a comparison of metric saturation as well as the performance of these metrics in differentiating protein simulations by mean conformational differences. We have produced MD trajectories to validate and apply the tools we have written. These trajectories include replicates of fragments of the FG-nucleoporins nsp1 and nup116 as well as several mutants with simulation times of 200-250 nanoseconds in implicit and explicit solvent. To compare these results with a simpler set of trajectories along a known spectrum of disorder, we simulated three sets of homopolymers with increasing conformational flexibility in explicit solvent.