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Optimization of Conformational Dynamics in an Epistatic Evolutionary Trajectory.

Authors
  • González, Mariano M1
  • Abriata, Luciano A1
  • Tomatis, Pablo E1
  • Vila, Alejandro J2
  • 1 IBR (Instituto de Biología Molecular y Celular de Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Ocampo y Esmeralda, Rosario, Argentina. , (Argentina)
  • 2 IBR (Instituto de Biología Molecular y Celular de Rosario), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Ocampo y Esmeralda, Rosario, Argentina Plataforma Argentina de Biología Estructural y Metabolómica (PLABEM), Ocampo y Esmeralda, Rosario, Argentina [email protected] , (Argentina)
Type
Published Article
Journal
Molecular Biology and Evolution
Publisher
Oxford University Press
Publication Date
Jul 01, 2016
Volume
33
Issue
7
Pages
1768–1776
Identifiers
DOI: 10.1093/molbev/msw052
PMID: 26983555
Source
Medline
Keywords
License
Unknown

Abstract

The understanding of protein evolution depends on the ability to relate the impact of mutations on molecular traits to organismal fitness. Biological activity and robustness have been regarded as important features in shaping protein evolutionary landscapes. Conformational dynamics, which is essential for protein function, has received little attention in the context of evolutionary analyses. Here we employ NMR spectroscopy, the chief experimental tool to describe protein dynamics at atomic level in solution at room temperature, to study the intrinsic dynamic features of a metallo- Β: -lactamase enzyme and three variants identified during a directed evolution experiment that led to an expanded substrate profile. We show that conformational dynamics in the catalytically relevant microsecond to millisecond timescale is optimized along the favored evolutionary trajectory. In addition, we observe that the effects of mutations on dynamics are epistatic. Mutation Gly262Ser introduces slow dynamics on several residues that surround the active site when introduced in the wild-type enzyme. Mutation Asn70Ser removes the slow dynamics observed for few residues of the wild-type enzyme, but increases the number of residues that undergo slow dynamics when introduced in the Gly262Ser mutant. These effects on dynamics correlate with the epistatic interaction between these two mutations on the bacterial phenotype. These findings indicate that conformational dynamics is an evolvable trait, and that proteins endowed with more dynamic active sites also display a larger potential for promoting evolution.

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