Geofold: Topology-based protein unfolding pathways capture the effects of engineered disulfides on kinetic stability
Vibin Ramakrishnan
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Biotechnology, Indian Institute of Technology, Guwahati 781039, India
Search for more papers by this authorSai Praveen Srinivasan
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180
Search for more papers by this authorSaeed M. Salem
Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York 12180
Computer Science Department, North Dakota State University, Fargo ND 58102
Search for more papers by this authorSuzanne J. Matthews
Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Computer Science & Engineering, Texas A&M University, College Station, TX 77843
Search for more papers by this authorWilfredo Colón
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180
Search for more papers by this authorMohammed Zaki
Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York 12180
Search for more papers by this authorCorresponding Author
Christopher Bystroff
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180===Search for more papers by this authorVibin Ramakrishnan
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Biotechnology, Indian Institute of Technology, Guwahati 781039, India
Search for more papers by this authorSai Praveen Srinivasan
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180
Search for more papers by this authorSaeed M. Salem
Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York 12180
Computer Science Department, North Dakota State University, Fargo ND 58102
Search for more papers by this authorSuzanne J. Matthews
Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Computer Science & Engineering, Texas A&M University, College Station, TX 77843
Search for more papers by this authorWilfredo Colón
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180
Search for more papers by this authorMohammed Zaki
Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York 12180
Search for more papers by this authorCorresponding Author
Christopher Bystroff
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Computer Science, Rensselaer Polytechnic Institute, Troy, New York 12180
Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180===Search for more papers by this authorAbstract
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. Proteins 2011. © 2012 Wiley Periodicals, Inc.
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