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Poor Person’s pH Simulation of Membrane Proteins

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Computational Design of Membrane Proteins

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2315))

Abstract

pH conditions are central to the functioning of all biomolecules. However, implications of pH changes are nontrivial on a molecular scale. Though a rigorous microscopic definition of pH exists, its implementation in classical molecular dynamics (MD) simulations is cumbersome, and more so in large integral membrane systems. In this chapter, an integrative pipeline is described that combines Multi-Conformation Continuum Electrostatics (MCCE) computations with MD simulations to capture the effect of transient protonation states on the coupled conformational changes in transmembrane proteins. The core methodologies are explained, and all the software required to set up this pipeline are outlined with their key parameters. All associated analyses of structure and function are provided using two case studies, namely those of bioenergetic complexes: NADH dehydrogenase (complex I) and Vo domain of V-type ATPase. The hybrid MCCE-MD pipeline has allowed the discovery of hydrogen bond networks, ligand binding pathways, and disease-causing mutations.

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Acknowledgements

The authors acknowledge start-up funds from the School of Molecular Sciences and Center for Applied Structure Discovery at Arizona State University, and the resources of the OLCF at the Oak Ridge National Laboratory, which is supported by the Office of Science at DOE under Contract No. DE-AC05-00OR22725, made available via the INCITE program. We also acknowledge NAMD and VMD developments supported by NIH (P41GM104601) and R01GM098243-02 for supporting our study of membrane proteins. AS acknowledges NSF (MCB-1942763) and NIH (R01GM095583). MG acknowledges NSF (MCB-1519640).

Author information

Authors and Affiliations

  1. The School of Molecular Sciences, Arizona State University, Tempe, AZ, USA

    Chitrak Gupta, John W. Vant & Abhishek Singharoy

  2. Biodesign Institute, Arizona State University, Tempe, AZ, USA

    Chitrak Gupta, John W. Vant & Abhishek Singharoy

  3. Department of Physics, City College of New York, New York, NY, USA

    Umesh Khaniya & M. R. Gunner

  4. Department of Physics, City University of New York, New York, NY, USA

    Umesh Khaniya & M. R. Gunner

  5. Center for Development of Therapeutics, Broad Institute, Cambridge, MA, USA

    Mrinal Shekhar

  6. Levich Institute, City College of New York, New York, NY, USA

    Junjun Mao

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  1. Chitrak Gupta
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  2. Umesh Khaniya
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  3. John W. Vant
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  4. Mrinal Shekhar
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  5. Junjun Mao
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  6. M. R. Gunner
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  7. Abhishek Singharoy
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Corresponding author

Correspondence to Abhishek Singharoy .

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Editors and Affiliations

  1. Department of Life Sciences, University of Coimbra, Coimbra, Portugal

    Irina S. Moreira

  2. BioISI, University of Lisboa, Lisboa, Portugal

    Miguel Machuqueiro

  3. Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

    Joana Mourão

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Gupta, C. et al. (2021). Poor Person’s pH Simulation of Membrane Proteins. In: Moreira, I.S., Machuqueiro, M., Mourão, J. (eds) Computational Design of Membrane Proteins. Methods in Molecular Biology, vol 2315. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1468-6_12

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  • DOI: https://doi.org/10.1007/978-1-0716-1468-6_12

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1467-9

  • Online ISBN: 978-1-0716-1468-6

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