Identification of potential allosteric binding sites in cathepsin K based on intramolecular communication
Gisele V. Rocha
Programa de Computação Científica, Vice-Presidência de Educação, Informação e Comunicação, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure Paris Saclay, Centre National de la Recherche Scientifique, Cachan, France
Search for more papers by this authorLeonardo S. Bastos
Programa de Computação Científica, Vice-Presidência de Educação, Informação e Comunicação, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Department of Infectious Diseases Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
Search for more papers by this authorCorresponding Author
Mauricio G. S. Costa
Programa de Computação Científica, Vice-Presidência de Educação, Informação e Comunicação, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure Paris Saclay, Centre National de la Recherche Scientifique, Cachan, France
Correspondence
Mauricio G. S. Costa, Programa de Computação Científica, Vice-Presidência de Educação, Informação e Comunicação, Fundação Oswaldo Cruz. Av. Brasil 4365, Rio de Janeiro 21040-222, Brazil.
Email: [email protected]
Search for more papers by this authorGisele V. Rocha
Programa de Computação Científica, Vice-Presidência de Educação, Informação e Comunicação, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure Paris Saclay, Centre National de la Recherche Scientifique, Cachan, France
Search for more papers by this authorLeonardo S. Bastos
Programa de Computação Científica, Vice-Presidência de Educação, Informação e Comunicação, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Department of Infectious Diseases Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
Search for more papers by this authorCorresponding Author
Mauricio G. S. Costa
Programa de Computação Científica, Vice-Presidência de Educação, Informação e Comunicação, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
Laboratoire de Biologie et de Pharmacologie Appliquée, Ecole Normale Supérieure Paris Saclay, Centre National de la Recherche Scientifique, Cachan, France
Correspondence
Mauricio G. S. Costa, Programa de Computação Científica, Vice-Presidência de Educação, Informação e Comunicação, Fundação Oswaldo Cruz. Av. Brasil 4365, Rio de Janeiro 21040-222, Brazil.
Email: [email protected]
Search for more papers by this authorFunding information: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Abstract
Network theory methods and molecular dynamics (MD) simulations are accepted tools to study allosteric regulation. Indeed, dynamic networks built upon correlation analysis of MD trajectories provide detailed information about communication paths between distant sites. In this context, we aimed to understand whether the efficiency of intramolecular communication could be used to predict the allosteric potential of a given site. To this end, we performed MD simulations and network theory analyses in cathepsin K (catK), whose allosteric sites are well defined. To obtain a quantitative measure of the efficiency of communication, we designed a new protocol that enables the comparison between properties related to ensembles of communication paths obtained from different sites. Further, we applied our strategy to evaluate the allosteric potential of different catK cavities not yet considered for drug design. Our predictions of the allosteric potential based on intramolecular communication correlate well with previous catK experimental and theoretical data. We also discuss the possibility of applying our approach to other proteins from the same family.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Supporting Information
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