Free energetics of rigid body association of ubiquitin binding domains: A biochemical model for binding mediated by hydrophobic interaction

Di Cui, Shuching Ou, Sandeep Patel

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Weak intermolecular interactions, such as hydrophobic associations, underlie numerous biomolecular recognition processes. Ubiquitin is a small protein that represents a biochemical model for exploring thermodynamic signatures of hydrophobic association as it is widely held that a major component of ubiquitin's binding to numerous partners is mediated by hydrophobic regions on both partners. Here, we use atomistic molecular dynamics simulations in conjunction with the Adaptive Biasing Force sampling method to compute potentials of mean force (the reversible work, or free energy, associated with the binding process) to investigate the thermodynamic signature of complexation in this well-studied biochemical model of hydrophobic association. We observe that much like in the case of a purely hydrophobic solute (i.e., graphene, carbon nanotubes), association is favored by entropic contributions from release of water from the interprotein regions. Moreover, association is disfavored by loss of enthalpic interactions, but unlike in the case of purely hydrophobic solutes, in this case protein-water interactions are lost and not compensated for by additional water-water interactions generated upon release of interprotein and moreso, hydration, water. We further find that relative orientations of the proteins that mutually present hydrophobic regions of each protein to its partner are favored over those that do not. In fact, the free energy minimum as predicted by a force field based method recapitulates the experimental NMR solution structure of the complex.

Original languageEnglish (US)
Pages (from-to)1453-1468
Number of pages16
JournalProteins: Structure, Function and Bioinformatics
Volume82
Issue number7
DOIs
StatePublished - Jul 2014

Keywords

  • Entropy contribution
  • Free energy
  • Hydrophobic interactions
  • Ubiquitin association
  • Ubiquitin binding domains

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Molecular Biology

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