Role of Conformational Motions in Enzyme Function: Selected Methodologies and Case Studies

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Abstract

It is now common knowledge that enzymes are mobile entities relying on complex atomic-scale dynamics and coordinated conformational events for proper ligand recognition and catalysis. However, the exact role of protein dynamics in enzyme function remains either poorly understood or difficult to interpret. This mini-review intends to reconcile biophysical observations and biological significance by first describing a number of common experimental and computational methodologies employed to characterize atomic-scale residue motions on various timescales in enzymes, and second by illustrating how the knowledge of these motions can be used to describe the functional behavior of enzymes and even act upon it. Two biologically relevant examples will be highlighted, namely the HIV-1 protease and DNA polymerase β enzyme systems.

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Most cited references 110

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Intrinsic dynamics of an enzyme underlies catalysis.

Elan Z. Eisenmesser, Oscar Millet, Wladimir Labeikovsky … (2005)

A unique feature of chemical catalysis mediated by enzymes is that the catalytically reactive atoms are embedded within a folded protein. Although current understanding of enzyme function has been focused on the chemical reactions and static three-dimensional structures, the dynamic nature of proteins has been proposed to have a function in catalysis. The concept of conformational substates has been described; however, the challenge is to unravel the intimate linkage between protein flexibility and enzymatic function. Here we show that the intrinsic plasticity of the protein is a key characteristic of catalysis. The dynamics of the prolyl cis-trans isomerase cyclophilin A (CypA) in its substrate-free state and during catalysis were characterized with NMR relaxation experiments. The characteristic enzyme motions detected during catalysis are already present in the free enzyme with frequencies corresponding to the catalytic turnover rates. This correlation suggests that the protein motions necessary for catalysis are an intrinsic property of the enzyme and may even limit the overall turnover rate. Motion is localized not only to the active site but also to a wider dynamic network. Whereas coupled networks in proteins have been proposed previously, we experimentally measured the collective nature of motions with the use of mutant forms of CypA. We propose that the pre-existence of collective dynamics in enzymes before catalysis is a common feature of biocatalysts and that proteins have evolved under synergistic pressure between structure and dynamics.

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Evolutionarily conserved networks of residues mediate allosteric communication in proteins.

Steven A Wall, Gürol Süel, Steve W. Lockless … (2002)

A fundamental goal in cellular signaling is to understand allosteric communication, the process by which signals originating at one site in a protein propagate reliably to affect distant functional sites. The general principles of protein structure that underlie this process remain unknown. Here, we describe a sequence-based statistical method for quantitatively mapping the global network of amino acid interactions in a protein. Application of this method for three structurally and functionally distinct protein families (G protein-coupled receptors, the chymotrypsin class of serine proteases and hemoglobins) reveals a surprisingly simple architecture for amino acid interactions in each protein family: a small subset of residues forms physically connected networks that link distant functional sites in the tertiary structure. Although small in number, residues comprising the network show excellent correlation with the large body of mechanistic data available for each family. The data suggest that evolutionarily conserved sparse networks of amino acid interactions represent structural motifs for allosteric communication in proteins.

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Repair and genetic consequences of endogenous DNA base damage in mammalian cells.

Deborah Barnes, Tomas L Lindahl (2004)

Living organisms dependent on water and oxygen for their existence face the major challenge of faithfully maintaining their genetic material under a constant attack from spontaneous hydrolysis and active oxygen species and from other intracellular metabolites that can modify DNA bases. Repair of endogenous DNA base damage by the ubiquitous base-excision repair pathway largely accounts for the significant turnover of DNA even in nonreplicating cells, and must be sufficiently accurate and efficient to preserve genome stability compatible with long-term cellular viability. The size of the mammalian genome has necessitated an increased complexity of repair and diversification of key enzymes, as revealed by gene knock-out mouse models. The genetic instability characteristic of cancer cells may be due, in part, to mutations in genes whose products normally function to ensure DNA integrity.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101695672

Journal ID (pubmed-jr-id): 45868

Journal ID (nlm-ta): Catalysts

Journal ID (iso-abbrev): Catalysts

Title: Catalysts (Basel, Switzerland)

ISSN (Electronic): 2073-4344

Publication date Nihms-submitted: 17 February 2017

Publication date (Electronic): 27 May 2016

Publication date (Print): June 2016

Publication date PMC-release: 31 March 2017

Volume: 6

Issue: 6

Electronic Location Identifier: 81

Affiliations

[1 ]INRS—Institut Armand-Frappier, Université du Québec, 531 Boul. des Prairies, Laval, QC H7V 1B7, Canada (C.N.)

[2 ]PROTEO, the Québec Network for Research on Protein Function, Engineering, and Applications, 1045 Avenue de la Médecine, Université Laval, Québec, QC G1V 0A6, Canada

[3 ]GRASP, the Groupe de Recherche Axé sur la Structure des Protéines, 3649 Promenade Sir William Osler, McGill University, Montréal, QC H3G 0B1, Canada

Author notes

[* ]Correspondence: nicolas.doucet@ 123456iaf.inrs.ca ; Tel.: +450-687-5010 (ext. 4212)

[†]

These authors contributed equally to this work.

Academic Editor: David D. Boehr

Article

Manuscript ID: NIHMS852606

DOI: 10.3390/catal6060081

PMC ID: 5375114

SO-VID: b87d6f2b-578a-426a-b759-18688e6cfee9

License:

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

Role of Conformational Motions in Enzyme Function: Selected Methodologies and Case Studies

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Most cited references 110

Intrinsic dynamics of an enzyme underlies catalysis.

Evolutionarily conserved networks of residues mediate allosteric communication in proteins.

Repair and genetic consequences of endogenous DNA base damage in mammalian cells.

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