Continuous Constant PH Molecular Dynamics Simulations of Transmembrane Proteins

Overview

Journal Methods Mol Biol

Specialty Molecular Biology

Date 2021 Apr 20

PMID 33877633

Citations 11

Authors

Yandong Huang

Jack A Henderson

Jana Shen

Affiliations

Soon will be listed here.

Abstract

Many membrane channels, transporters, and receptors utilize a pH gradient or proton coupling to drive functionally relevant conformational transitions. Conventional molecular dynamics simulations employ fixed protonation states, thus neglecting the coupling between protonation and conformational equilibria. Here we describe the membrane-enabled hybrid-solvent continuous constant pH molecular dynamics method for capturing atomic details of proton-coupled conformational dynamics of transmembrane proteins. Example protocols from our recent application studies of proton channels and ion/substrate transporters are discussed.

Citing Articles

Interior pH-sensing residue of human voltage-gated proton channel H1 is histidine 168.

Shen M, Huang Y, Cai Z, Cherny V, DeCoursey T, Shen J Biophys J. 2024; 123(24):4211-4220.

PMID: 39054673 PMC: 11700365. DOI: 10.1016/j.bpj.2024.07.027.

Energy coupling and stoichiometry of Zn/H antiport by the prokaryotic cation diffusion facilitator YiiP.

Hussein A, Fan S, Lopez-Redondo M, Kenney I, Zhang X, Beckstein O Elife. 2023; 12.

PMID: 37906094 PMC: 10617992. DOI: 10.7554/eLife.87167.

Comparative Performance of High-Throughput Methods for Protein p Predictions.

Wei W, Hogues H, Sulea T J Chem Inf Model. 2023; 63(16):5169-5181.

PMID: 37549424 PMC: 10466379. DOI: 10.1021/acs.jcim.3c00165.

PKAD-2: New entries and expansion of functionalities of the database of experimentally measured pKa's of proteins.

Ancona N, Bastola A, Alexov E J Comput Biophys Chem. 2023; 22(5):515-524.

PMID: 37520074 PMC: 10373500. DOI: 10.1142/s2737416523500230.

A Guide to the Continuous Constant pH Molecular Dynamics Methods in Amber and CHARMM [Article v1.0].

Henderson J, Liu R, Harris J, Huang Y, de Oliveira V, Shen J Living J Comput Mol Sci. 2023; 4(1).

PMID: 36776714 PMC: 9910290. DOI: 10.33011/livecoms.4.1.1563.

References

Ramsey I, Moran M, Chong J, Clapham D . A voltage-gated proton-selective channel lacking the pore domain. Nature. 2006; 440(7088):1213-6. PMC: 4084761. DOI: 10.1038/nature04700. View

Ludwig M, Vanek M, Guerini D, Gasser J, Jones C, Junker U . Proton-sensing G-protein-coupled receptors. Nature. 2003; 425(6953):93-8. DOI: 10.1038/nature01905. View

Lomize M, Lomize A, Pogozheva I, Mosberg H . OPM: orientations of proteins in membranes database. Bioinformatics. 2006; 22(5):623-5. DOI: 10.1093/bioinformatics/btk023. View

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View

Lee C, Yashiro S, Dotson D, Uzdavinys P, Iwata S, Sansom M . Crystal structure of the sodium-proton antiporter NhaA dimer and new mechanistic insights. J Gen Physiol. 2014; 144(6):529-44. PMC: 4242812. DOI: 10.1085/jgp.201411219. View

Arthur E, Brooks 3rd C . Efficient implementation of constant pH molecular dynamics on modern graphics processors. J Comput Chem. 2016; 37(24):2171-80. PMC: 4981528. DOI: 10.1002/jcc.24435. View

Brunger A, Karplus M . Polar hydrogen positions in proteins: empirical energy placement and neutron diffraction comparison. Proteins. 1988; 4(2):148-56. DOI: 10.1002/prot.340040208. View

DeCoursey T, Hosler J . Philosophy of voltage-gated proton channels. J R Soc Interface. 2013; 11(92):20130799. PMC: 3899857. DOI: 10.1098/rsif.2013.0799. View

Eastman P, Swails J, Chodera J, McGibbon R, Zhao Y, Beauchamp K . OpenMM 7: Rapid development of high performance algorithms for molecular dynamics. PLoS Comput Biol. 2017; 13(7):e1005659. PMC: 5549999. DOI: 10.1371/journal.pcbi.1005659. View

10.

Wallace J, Shen J . Predicting pKa values with continuous constant pH molecular dynamics. Methods Enzymol. 2011; 466:455-75. DOI: 10.1016/S0076-6879(09)66019-5. View

11.

Mager T, Rimon A, Padan E, Fendler K . Transport mechanism and pH regulation of the Na+/H+ antiporter NhaA from Escherichia coli: an electrophysiological study. J Biol Chem. 2011; 286(26):23570-81. PMC: 3123120. DOI: 10.1074/jbc.M111.230235. View

12.

Harris R, Tsai C, Ellis C, Shen J . Proton-Coupled Conformational Allostery Modulates the Inhibitor Selectivity for β-Secretase. J Phys Chem Lett. 2017; 8(19):4832-4837. PMC: 5713904. DOI: 10.1021/acs.jpclett.7b02309. View

13.

Wallace J, Shen J . Unraveling A Trap-and-Trigger Mechanism in the pH-Sensitive Self-Assembly of Spider Silk Proteins. J Phys Chem Lett. 2012; 3(5):658-662. PMC: 3410443. DOI: 10.1021/jz2016846. View

14.

Chen W, Huang Y, Shen J . Conformational Activation of a Transmembrane Proton Channel from Constant pH Molecular Dynamics. J Phys Chem Lett. 2016; 7(19):3961-3966. PMC: 5718886. DOI: 10.1021/acs.jpclett.6b01853. View

15.

Im W, Lee M, Brooks 3rd C . Generalized born model with a simple smoothing function. J Comput Chem. 2003; 24(14):1691-702. DOI: 10.1002/jcc.10321. View

16.

Hunte C, Screpanti E, Venturi M, Rimon A, Padan E, Michel H . Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH. Nature. 2005; 435(7046):1197-202. DOI: 10.1038/nature03692. View

17.

Jo S, Kim T, Im W . Automated builder and database of protein/membrane complexes for molecular dynamics simulations. PLoS One. 2007; 2(9):e880. PMC: 1963319. DOI: 10.1371/journal.pone.0000880. View

18.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

19.

MacKerell Jr A, Feig M, Brooks 3rd C . Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J Comput Chem. 2004; 25(11):1400-15. DOI: 10.1002/jcc.20065. View

20.

Mori T, Ogushi F, Sugita Y . Analysis of lipid surface area in protein-membrane systems combining Voronoi tessellation and Monte Carlo integration methods. J Comput Chem. 2011; 33(3):286-93. DOI: 10.1002/jcc.21973. View