title: Analysis of Multidomain Protein Dynamics.
abstract: Proteins with a modular architecture of multiple domains connected by linkers often exhibit diversity in the relative positions of domains, while the domain tertiary structure remains unchanged. The biological function of these modular proteins, or the regulation of their activity, depends on the variation in domain orientation and separation. Accordingly, careful characterization of interdomain motion and correlated fluctuations of multidomain systems is relevant for understanding the functional behavior of modular proteins. Molecular dynamics (MD) simulations provides a powerful approach to study these motions in atomic detail. Nevertheless, the common procedure for analyzing fluctuations from MD simulations after rigid-body alignment fails for multidomain proteins; it greatly overestimates correlated positional fluctuations in the presence of relative domain motion. We show here that expressing the atomic motions of a multidomain protein as a combination of displacement within the domain reference frame and motion of the relative domains correctly separates the internal motions to allow a useful description of correlated fluctuations. We illustrate the methodology of separating the domain fluctuations and local fluctuations by application to the tandem SH2 domains of human Syk protein kinase and by characterizing an effect of phosphorylation on the dynamics. Correlated motions are assessed from a distance covariance rather than the more common vector-coordinate covariance. The approach makes it possible to calculate the proper correlations in fluctuations internal to a domain as well as between domains.
authors.affiliation: Bioinformatics and Computational Biosciences Branch, Rocky Mountain Laboratories, NIAID, National Institutes of Health , Hamilton, Montana 59840, United States.
authors.forename: Amitava
authors.initials: A
authors.lastname: Roy
authors.forename: Duy P
authors.initials: DP
authors.lastname: Hua
authors.forename: Carol Beth
authors.initials: CB
authors.lastname: Post
mesh_terms: D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D000072377:Syk Kinase; D018909:src Homology Domains
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase