title: Geofold: topology-based protein unfolding pathways capture the effects of engineered disulfides on kinetic stability.
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.
authors.affiliation: Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA.
authors.forename: Vibin
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Sai Praveen
authors.initials: SP
authors.lastname: Srinivasan
authors.forename: Saeed M
authors.initials: SM
authors.lastname: Salem
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Matthews
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Colón
authors.forename: Mohammed
authors.initials: M
authors.lastname: Zaki
authors.forename: Christopher
authors.initials: C
authors.lastname: Bystroff
mesh_terms: D001407:Bacillus / Q000201:enzymology / Q000235:genetics; D001426:Bacterial Proteins; D017122:Bacteriophage T4 / Q000201:enzymology / Q000235:genetics; D004220:Disulfides / Q000737:chemistry*; D019277:Entropy; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D007700:Kinetics; D008958:Models, Molecular; D009113:Muramidase / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D011487:Protein Conformation; D055550:Protein Stability; D058767:Protein Unfolding; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D012260:Ribonucleases / Q000737:chemistry / Q000235:genetics; D012984:Software; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000235:genetics
chemical_list: D001426:Bacterial Proteins; D004220:Disulfides; D011506:Proteins; D013762:Tetrahydrofolate Dehydrogenase; D012260:Ribonucleases; C019760:Bacillus amyloliquefaciens ribonuclease; D009113:Muramidase