Identification of Dynamic Structural Domains in Proteins, Analysis of Local Bond Flexibility,and Application for Interpretation of NMR Experiments
National Institute for Nanotechnology, CA
Keywords: protein conformations, multiscale modelig, generalised Langevin dynamics, interpretation of NMR measurements
Abstract:A novel theoretical methodology is introduced to cidentify dynamic structural domains and analyze local flexibility in proteins. The methodology employs a multiscale approach combining identification of essential collective coordinates based on the covariance analysis of molecular dynamics trajectories, construction of the Mori projection operator with these essential coordinates, and analysis of the corresponding generalized Langevin equations. Because the approach is based on a rigorous theory, the outcomes are physically transparent: the dynamic structural domains are associated with regions of relative rigidity in the protein, whereas off-domain regions are relatively soft. This allows introducing a score for the local flexibility in the macromolecule with atomic-level resolution. In this contribution, the background of the methodology is presented and examples of applications are given. These include identification of structural domains and characterization of the flexibility in protein G and cellular prion proteins. The results are compared with published NMR experiments, including model-free order parameters, random coil indexes, and residual dipolar coupling analyses for the proteins considered. It is demonstrated that the methodology has a strong potential for further applications as a rigorous, dynamically based numeric score and characterization tool in structural biology, bioinformatics, in-silico drug design, and design of bionanoMEMS.