Incorporation of side chain flexibility into protein binding pockets using MTflex |
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| Institution: | 1. Department of Chemistry, Michigan State University, 578 South Shaw Lane, East Lansing, MI 48824, United States;2. Institute for Cyber Enabled Research, Michigan State University, 567 Wilson Road, East Lansing, MI 48824, United States;1. Department of Computer Science, Abdul Wali Khan University Mardan, Pakistan;2. Department of Computer Science, National University of Computer and Emerging Science, Peshawar, Pakistan;1. Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan;2. Laboratory of Veterinary Histopathology, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-8508, Japan;3. Biological Safety Research Center, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan;1. Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, International Campus, Mashhad, Iran;2. Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran;3. Research and Technology Center of Biomolecules, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, Iran;1. Department of Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA;2. Department of Physics, Freie Universität Berlin, Berlin 14195, Germany;3. Interfaculty Institute of Biochemistry, Eberhard Karls University Tübingen, Tübingen 72074, Germany;4. Laboratory of Physical Chemistry, ETH Zürich, Zürich 8093, Switzerland;1. Neurosurgery-Neurotraumatology Unit, University Hospital of Parma, Viale Gramsci 14, 43100 Parma, Italy;2. Emergency Neurosurgery Unit, IRCCS “Arcispedale Santa Maria Nuova” of Reggio Emilia, Viale Risorgimento 80, 42123 Reggio Emilia, Italy;3. University of Parma, Department of Oncohemathology, “Guglielmo da Saliceto” Hospital of Piacenza, Via Taverna 49, 29121 Piacenza, Italy;4. Division of Neurosurgery, Department of Neurosciences Head and Neck Surgery, S. Camillo Hospital, Rome, Italy;5. Centre for Spinal Studies and Surgery, Queen''s Medical Centre, Nottingham, UK;6. Laboratory of Molecular Biology, IRCCS “Arcispedale Santa Maria Nuova” of Reggio Emilia, Viale Risorgimento 80, 42123 Reggio Emilia, Italy;7. Neuroradiology Unit, IRCCS “Arcispedale Santa Maria Nuova” of Reggio Emilia, Viale Risorgimento 80, 42123 Reggio Emilia, Italy;8. Neuroradiology Unit, Diagnostic Department, University Hospital of Parma, Viale Gramsci 14, 43100 Parma, Italy;9. Neurology Unit, Neuromotor Department, IRCCS “Arcispedale Santa Maria Nuova” of Reggio Emilia, Viale Risorgimento 80, 42123 Reggio Emilia, Italy;10. Neuroscience Department, University Hospital of Parma, Viale Gramsci 14, 43100 Parma, Italy;11. Unit of Pathology, IRCCS “Arcispedale Santa Maria Nuova” of Reggio Emilia, Viale Risorgimento 80, 42123 Reggio Emilia, Italy;12. Unit of Pathology, Department of Biomedical, Biotechnology and Translational Sciences, University Hospital of Parma, Viale Gramsci 14, 43100 Parma, Italy;13. Unit of Radiotherapy, University Hospital of Parma, Viale Gramsci 14, 43100 Parma, Italy;14. Unit of Oncology, University Hospital of Parma, Viale Gramsci 14, 43100 Parma, Italy;1. Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, United States;2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, United States |
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| Abstract: | The plasticity of active sites plays a significant role in drug recognition and binding, but the accurate incorporation of ‘receptor flexibility’ remains a significant computational challenge. Many approaches have been put forward to address receptor flexibility in docking studies by generating relevant ensembles on the energy surface. Herein, we describe the Movable Type with flexibility (MTflex) method that generates ensembles on the more relevant free energy surface in a computationally tractable manner. This novel approach enumerates conformational states based on side chain flexibility and then estimates their relative free energies using the MT methodology. The resultant conformational states can then be used in subsequent docking and scoring exercises. In particular, we demonstrate that using the MTflex ensembles improves MT’s ability to predict binding free energies over docking only to the crystal structure. |
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| Keywords: | Movable Type method Receptor flexibility Binding free energy Docking Scoring |
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