Title: Protein Conformational Populations and Functionally Relevant Substates

Abstract

Functioning proteins do not remain fixed in a unique structure, rather they sample a range of conformations facilitated by motions within the protein. Even in the native state, a protein exists as a collection of interconverting conformations driven by thermodynamic fluctuations. Motions on the fast time scale allow a protein to sample conformations in the nearby area of its conformational landscape, while motions on slower time scales give it access to conformations in distal areas of the landscape. Emerging evidence indicates that protein landscapes contain conformational substates with dynamic and structural features that support the designated function of the protein. Nuclear magnetic resonance (NMR) experiments provide information about conformational ensembles of proteins. X-ray crystallography allows researchers to identify the most populated states along the landscape, and computational simulations give atom-level information about the conformational substates of different proteins. This ability to characterize and obtain quantitative information about the conformational substates and the populations of proteins within them is allowing researchers to better understand the relationship between protein structure and dynamics and the mechanisms of protein function. In this Account, we discuss recent developments and challenges in the characterization of functionally relevant conformational populations and substates of proteins. In some enzymes,more » the sampling of functionally relevant conformational substates is connected to promoting the overall mechanism of catalysis. For example, the conformational landscape of the enzyme dihydrofolate reductase hasmultiple substates, which facilitate the binding and the release of the cofactor and substrate and catalyze the hydride transfer. For the enzyme cyclophilin A, computational simulations reveal that the long time scale conformational fluctuations enable the enzyme to access conformational substates that allow it to attain the transition state, therefore promoting the reaction mechanism. Long-term, this emerging view of proteins with conformational substates has broad implications for improving our understanding of enzymes, enzyme engineering, and better drug design. Researchers have already used photoactivation to modulate protein conformations as a strategy to develop a hypercatalytic enzyme. Furthermore, the alteration of the conformational substates through binding of ligands at locations other than the active site provides the basis for the design of new medicines through allosteric modulation.« less

Authors:

Ramanathan, Arvind ^[1]; Savol, Andrej ^[2]; Burger, Virginia ^[2]; Chennubhotla, Chakra S. ^[3]; Agarwal, Pratul K. ^[4]

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+ Show Author Affiliations

1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Computational Science and Engineering Division
2. Carnegie Mellon Univ., Pittsburgh, PA (United States). Computational Biology; Univ. of Pittsburgh, PA (United States). Dept. of Computational and Systems Biology
3. Univ. of Pittsburgh, PA (United States). Dept. of Computational and Systems Biology
4. Annavitas Biosciences, Knoxville, TN (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Computational Biology Inst., and Computer Science and Mathematics Division

Publication Date:

2013-08-29

Research Org.:

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Org.:

USDOE Office of Science (SC)

OSTI Identifier:

1565147

Resource Type:

Journal Article: Accepted Manuscript

Journal Name:

Accounts of Chemical Research

Additional Journal Information:

Journal Volume: 47; Journal Issue: 1; Journal ID: ISSN 0001-4842

Publisher:

American Chemical Society

Country of Publication:

United States

Language:

English

Subject:

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY