Calculation of the free energy and cooperativity of protein folding. Academic Article uri icon

Overview

abstract

  • Calculation of the free energy of protein folding and delineation of its pre-organization are of foremost importance for understanding, predicting and designing biological macromolecules. Here, we introduce an energy smoothing variant of parallel tempering replica exchange Monte Carlo (REMS) that allows for efficient configurational sampling of flexible solutes under the conditions of molecular hydration. Its usage to calculate the thermal stability of a model globular protein, Trp cage TC5b, achieves excellent agreement with experimental measurements. We find that the stability of TC5b is attained through the coupled formation of local and non-local interactions. Remarkably, many of these structures persist at high temperature, concomitant with the origin of native-like configurations and mesostates in an otherwise macroscopically disordered unfolded state. Graph manifold learning reveals that the conversion of these mesostates to the native state is structurally heterogeneous, and that the cooperativity of their formation is encoded largely by the unfolded state ensemble. In all, these studies establish the extent of thermodynamic and structural pre-organization of folding of this model globular protein, and achieve the calculation of macromolecular stability ab initio, as required for ab initio structure prediction, genome annotation, and drug design.

publication date

  • May 16, 2007

Research

keywords

  • Protein Folding
  • Proteins

Identity

PubMed Central ID

  • PMC1865387

Scopus Document Identifier

  • 55849087551

Digital Object Identifier (DOI)

  • 10.1371/journal.pone.0000446

PubMed ID

  • 17505540

Additional Document Info

volume

  • 2

issue

  • 5