Multiscale reactive molecular dynamics simulation of proton transport in proteins /

Multiscale reactive molecular dynamics simulation of proton transport in proteins /

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Bibliographic Details
Author / Creator:Liang, Ruibin, author.
Imprint:2016.
Ann Arbor : ProQuest Dissertations & Theses, 2016
Description:1 electronic resource (316 pages)
Language:English
Format: E-Resource Dissertations
Local Note:School code: 0330
URL for this record:http://pi.lib.uchicago.edu/1001/cat/bib/10862872
Hidden Bibliographic Details
Other authors / contributors:University of Chicago. degree granting institution.
ISBN:9781339873640
Notes:Advisors: Gregory A. Voth Committee members: Ka Yee C. Lee; Suri Vaikuntanathan.
This item is not available from ProQuest Dissertations & Theses.
Dissertation Abstracts International, Volume: 77-10(E), Section: B.
English
Summary:The process of proton solvation and transport is involved in a wide array of phenomena. Although seemingly simple, it is a complex process that continues to engage research efforts. One unique aspect of the molecular mechanism of proton solvation and transport is that the hydrated proton is able to hop between neighboring water molecules by "Grotthuss shuttling", giving rise to anomalously high diffusion rate of protons compared to other simple cations. In addition, the hydrated proton is able to dynamically delocalize the excess charge defect over multiple water molecules within several solvation shells. Inside proteins, the structure and dynamics of the residues and water molecules that mediate proton transport are strongly influenced by the electrostatic and hydrophobic environment in the protein cavities. Hence, proton transport in proteins is very different from that in aqueous bulk solution and displays many interesting behaviors. Explicitly simulating proton transport in proteins is an inherently challenging problem. It requires both the explicit treatment of the excess proton, including its charge defect delocalization and Grotthuss shuttling through inhomogeneous moieties (water and amino acid residues), and extensive sampling of slow conformational changes of both the protein and water clusters inside protein cavities.
In recent years, the self-consistent charge density functional tight binding (SCC-DFTB) method has been increasingly applied to study proton transport (PT) in biological environments. However, recent studies revealing some significant limitations of SCC-DFTB for proton and hydroxide solvation and transport in bulk aqueous systems call into question its accuracy for simulating PT in biological systems. The current work benchmarks the SCC-DFTB/MM method against more accurate DFT/MM by simulating PT in a synthetic leucine-serine channel (LS2), which emulates the structure and function of biomolecular proton channels. It is observed that SCC-DFTB/MM produces over-coordinated and less structured pore water, an over-coordinated excess proton, weak hydrogen bonds around the excess proton charge defect and qualitatively different PT dynamics. Similar issues are demonstrated for PT in a carbon nanotube, indicating that the inaccuracies found for SCC-DFTB are not due to the point charge based QM/MM electrostatic coupling scheme, but rather to the approximations of the semiempirical method itself. The results presented in this work highlight the limitations of the present form of the SCC-DFTB/MM approach for simulating PT processes in biological protein or channel-like environments, while providing benchmark results that may lead to an improvement of the underlying method.
An alternative approach that explicitly accounts for the reactive nature of the hydrated excess proton is multiscale reactive molecular dynamics (MS-RMD) method. In this approach, quantum mechanical forces from targeted quantum mechanics/molecular mechanics (QM/MM) calculations are bridged, in a multiscale fashion via a variational mathematical framework, into the reactive MD algorithm for the dynamics of system nuclei, thus allowing efficient and accurate description of Grotthuss shuttling and charge delocalization during PT. Herein, we have used a synthesis of the MS-RMD, QM/MM and classical MD simulations to study the PT mechanism in the influenza A virus M2 channel (AM2), which is crucial in the viral life cycle. Despite many previous experimental and computational studies, the mechanism of the activating process in which proton permeation acidifies the virion to release the viral RNA and core proteins is not well understood. We report, to our knowledge, the first complete free-energy profiles for PT through the entire AM2 transmembrane domain at various pH values, including explicit treatment of excess proton charge delocalization and shuttling through the His37 tetrad. The free-energy profiles reveal that the excess proton must overcome a large free- energy barrier to diffuse to the His37 tetrad, where it is stabilized in a deep minimum reflecting the delocalization of the excess charge among the histidines and the cost of shuttling the proton past them. At lower pH values the His37 tetrad has a larger total charge that increases the channel width, hydration, and solvent dynamics, in agreement with recent 2D-IR spectroscopic studies. The PT barrier becomes smaller, despite the increased charge repulsion, due to backbone expansion and the more dynamic pore water molecules. The calculated conductances are in quantitative agreement with recent experimental measurements. In addition, the free-energy profiles and conductances for PT in several mutants provide insights for explaining our findings and those of previous experimental mutagenesis studies. (Abstract shortened by ProQuest.).

MARC

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510 4 |a Dissertation Abstracts International,   |c Volume: 77-10(E), Section: B. 
520 |a The process of proton solvation and transport is involved in a wide array of phenomena. Although seemingly simple, it is a complex process that continues to engage research efforts. One unique aspect of the molecular mechanism of proton solvation and transport is that the hydrated proton is able to hop between neighboring water molecules by "Grotthuss shuttling", giving rise to anomalously high diffusion rate of protons compared to other simple cations. In addition, the hydrated proton is able to dynamically delocalize the excess charge defect over multiple water molecules within several solvation shells. Inside proteins, the structure and dynamics of the residues and water molecules that mediate proton transport are strongly influenced by the electrostatic and hydrophobic environment in the protein cavities. Hence, proton transport in proteins is very different from that in aqueous bulk solution and displays many interesting behaviors. Explicitly simulating proton transport in proteins is an inherently challenging problem. It requires both the explicit treatment of the excess proton, including its charge defect delocalization and Grotthuss shuttling through inhomogeneous moieties (water and amino acid residues), and extensive sampling of slow conformational changes of both the protein and water clusters inside protein cavities. 
520 |a In recent years, the self-consistent charge density functional tight binding (SCC-DFTB) method has been increasingly applied to study proton transport (PT) in biological environments. However, recent studies revealing some significant limitations of SCC-DFTB for proton and hydroxide solvation and transport in bulk aqueous systems call into question its accuracy for simulating PT in biological systems. The current work benchmarks the SCC-DFTB/MM method against more accurate DFT/MM by simulating PT in a synthetic leucine-serine channel (LS2), which emulates the structure and function of biomolecular proton channels. It is observed that SCC-DFTB/MM produces over-coordinated and less structured pore water, an over-coordinated excess proton, weak hydrogen bonds around the excess proton charge defect and qualitatively different PT dynamics. Similar issues are demonstrated for PT in a carbon nanotube, indicating that the inaccuracies found for SCC-DFTB are not due to the point charge based QM/MM electrostatic coupling scheme, but rather to the approximations of the semiempirical method itself. The results presented in this work highlight the limitations of the present form of the SCC-DFTB/MM approach for simulating PT processes in biological protein or channel-like environments, while providing benchmark results that may lead to an improvement of the underlying method. 
520 |a An alternative approach that explicitly accounts for the reactive nature of the hydrated excess proton is multiscale reactive molecular dynamics (MS-RMD) method. In this approach, quantum mechanical forces from targeted quantum mechanics/molecular mechanics (QM/MM) calculations are bridged, in a multiscale fashion via a variational mathematical framework, into the reactive MD algorithm for the dynamics of system nuclei, thus allowing efficient and accurate description of Grotthuss shuttling and charge delocalization during PT. Herein, we have used a synthesis of the MS-RMD, QM/MM and classical MD simulations to study the PT mechanism in the influenza A virus M2 channel (AM2), which is crucial in the viral life cycle. Despite many previous experimental and computational studies, the mechanism of the activating process in which proton permeation acidifies the virion to release the viral RNA and core proteins is not well understood. We report, to our knowledge, the first complete free-energy profiles for PT through the entire AM2 transmembrane domain at various pH values, including explicit treatment of excess proton charge delocalization and shuttling through the His37 tetrad. The free-energy profiles reveal that the excess proton must overcome a large free- energy barrier to diffuse to the His37 tetrad, where it is stabilized in a deep minimum reflecting the delocalization of the excess charge among the histidines and the cost of shuttling the proton past them. At lower pH values the His37 tetrad has a larger total charge that increases the channel width, hydration, and solvent dynamics, in agreement with recent 2D-IR spectroscopic studies. The PT barrier becomes smaller, despite the increased charge repulsion, due to backbone expansion and the more dynamic pore water molecules. The calculated conductances are in quantitative agreement with recent experimental measurements. In addition, the free-energy profiles and conductances for PT in several mutants provide insights for explaining our findings and those of previous experimental mutagenesis studies. (Abstract shortened by ProQuest.). 
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