Geofold: Topology-based protein unfolding pathways capture the effects of engineered disulfides on kinetic stability

Vibin Ramakrishnan, Sai Praveen Srinivasan, Saeed M. Salem, Suzanne J. Matthews, Wilfredo Colón, Mohammed Zaki, C. Bystroff

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11 Citations (Scopus)

Abstract

Protein unfolding is modeled as an ensemble of pathways, where each step in each pathway is the addition of one topologically possible conformational degree of freedom. Starting with a known protein structure, GeoFold hierarchically partitions (cuts) the native structure into substructures using revolute joints and translations. The energy of each cut and its activation barrier are calculated using buried solvent accessible surface area, side chain entropy, hydrogen bonding, buried cavities, and backbone degrees of freedom. A directed acyclic graph is constructed from the cuts, representing a network of simultaneous equilibria. Finite difference simulations on this graph simulate native unfolding pathways. Experimentally observed changes in the unfolding rates for disulfide mutants of barnase, T4 lysozyme, dihydrofolate reductase, and factor for inversion stimulation were qualitatively reproduced in these simulations. Detailed unfolding pathways for each case explain the effects of changes in the chain topology on the folding energy landscape. GeoFold is a useful tool for the inference of the effects of disulfide engineering on the energy landscape of protein unfolding.

Original languageEnglish
Pages (from-to)920-934
Number of pages15
JournalProteins: Structure, Function and Bioinformatics
Volume80
Issue number3
DOIs
Publication statusPublished - 1 Mar 2012
Externally publishedYes

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Keywords

  • Barnase
  • Configurational entropy
  • DHFR
  • Kinetic stability
  • Lysozyme FIS
  • Pathways
  • Topology

ASJC Scopus subject areas

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Cite this

Ramakrishnan, V., Srinivasan, S. P., Salem, S. M., Matthews, S. J., Colón, W., Zaki, M., & Bystroff, C. (2012). Geofold: Topology-based protein unfolding pathways capture the effects of engineered disulfides on kinetic stability. Proteins: Structure, Function and Bioinformatics, 80(3), 920-934. https://doi.org/10.1002/prot.23249