The Role of Conformational Dynamics and Allostery in Modulating Protein Evolution

Paul Campitelli, Tushar Modi, Sudhir Kumar, S. Banu Ozkan

Research output: Contribution to journalReview article

2 Scopus citations

Abstract

Advances in sequencing techniques and statistical methods have made it possible not only to predict sequences of ancestral proteins but also to identify thousands of mutations in the human exome, some of which are disease associated. These developments have motivated numerous theories and raised many questions regarding the fundamental principles behind protein evolution, which have been traditionally investigated horizontally using the tip of the phylogenetic tree through comparative studies of extant proteins within a family. In this article, we review a vertical comparison of the modern and resurrected ancestral proteins. We focus mainly on the dynamical properties responsible for a protein's ability to adapt new functions in response to environmental changes. Using the Dynamic Flexibility Index and the Dynamic Coupling Index to quantify the relative flexibility and dynamic coupling at a site-specific, single-amino-acid level, we provide evidence that the migration of hinges, which are often functionally critical rigid sites, is a mechanism through which proteins can rapidly evolve. Additionally, we show that disease-associated mutations in proteins often result in flexibility changes even at positions distal from mutational sites, particularly in the modulation of active site dynamics.

Original languageEnglish (US)
Pages (from-to)267-288
Number of pages22
JournalAnnual review of biophysics
Volume49
DOIs
StatePublished - May 6 2020

Keywords

  • Conformational dynamics
  • allostery
  • molecular dynamics simulation
  • protein design
  • protein evolution
  • protein flexibility

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Bioengineering
  • Biochemistry
  • Cell Biology

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