Investigation of intrinsic dynamics of enzymes involved in metabolic pathways using coarse-grained normal mode analysis

Sarah M. Meeuwsen, An N. Hodac, Lauren M. Adams, Ryan D. McMunn, Maxwell S. Anschutz, Kari J. Carothers, Rachel E. Egdorf, Peter M. Hanneman, Jonathan P. Kitzrow, Cynthia K. Keonigsberg, Oscar Lopez-Martinez, Paul A. Matthew (+7 others)
2017 Cogent Biology  
Intrinsic dynamics of proteins are known to play important roles in their function. In particular, collective dynamics of a protein, which are defined by the protein's overall architecture, are important in promoting the active site conformation that favors substrate binding and effective catalysis. The primary sequence of a protein, which determines its three-dimensional structure, encodes unique dynamics. The intrinsic dynamics of a protein actually link protein structure to its function. In
more » ... he present study, coarse-grained normal mode analysis was performed to examine the intrinsic dynamic patterns of 24 different enzymes involved in primary metabolic pathways. We observed that each metabolic enzyme exhibits unique patterns of motions, which are conserved across multiple species and functionally relevant. Dynamic cross-correlation matrices (DCCMs) are visibly identical for a given enzyme family but significantly different from DCCMs of other protein families, reinforcing that proteins with similar function exhibit a similar pattern of motions. The present work also reasserted that correct identification of unknown proteins is possible based on their intrinsic mobility patterns. Our research is focused on the simple questionhow protein motions influence substrate binding and catalysis. The relationship between protein dynamics and its role in function (molecular recognition, catalysis, and allostery) is an evolving perspective in enzymology. For the past several years, we have been investigating the interplay of protein dynamics and enzymatic processes using computations and experiments. In particular, we are exploring how dynamics of different domains modulate substrate recognition, catalysis, and allosteric communication in multi-domain enzymes. Our overall goal is to advance the drug design and screening process, by taking into consideration proteins' intrinsic flexibility.
doi:10.1080/23312025.2017.1291877 fatcat:l54k4gq5tnb3ta64bdxpr6kq7m