@article {704, title = {An Improved Multistate Empirical Valence Bond Model for Aqueous Proton Solvation and Transport}, journal = {J. Phys. Chem. B}, volume = {112}, year = {2008}, pages = {467-482}, doi = {10.1021/jp076658h}, author = {Y. Wu and Chen, H. and Wang, F. and Paesani, F. and G. A. Voth} } @article {422, title = {Charge Delocalization in Proton Channels, I: the Aquaporin Channels and Proton Blockage}, journal = {Biophys J}, volume = {92}, number = {1}, year = {2007}, note = {Chen, Hanning Ilan, Boaz Wu, Yujie Zhu, Fangqiang Schulten, Klaus Voth, Gregory A 2 P41 RR05969/RR/NCRR NIH HHS/United States R01 GM067887/GM/NIGMS NIH HHS/United States R01-GM53148/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. United States Biophysical journal Biophys J. 2007 Jan 1;92(1):46-60. Epub 2006 Oct 20.}, pages = {46-60}, abstract = {

The explicit contribution to the free energy barrier and proton conductance from the delocalized nature of the excess proton is examined in aquaporin channels using an accurate all-atom molecular dynamics computer simulation model. In particular, the channel permeation free energy profiles are calculated and compared for both a delocalized (fully Grotthuss shuttling) proton and a classical (nonshuttling) hydronium ion along two aquaporin channels, Aqp1 and GlpF. To elucidate the effects of the bipolar field thought to arise from two alpha-helical macrodipoles on proton blockage, free energy profiles were also calculated for computational mutants of the two channels where the bipolar field was eliminated by artificially discharging the backbone atoms. Comparison of the free energy profiles between the proton and hydronium cases indicates that the magnitude of the free energy barrier and position of the barrier peak for the fully delocalized and shuttling proton are somewhat different from the case of the (localized) classical hydronium. The proton conductance through the two aquaporin channels is also estimated using Poisson-Nernst-Planck theory for both the Grotthuss shuttling excess proton and the classical hydronium cation.

}, keywords = {Aquaporin 1/*chemistry Aquaporins/*chemistry Biological Transport Biophysics/*methods Escherichia coli Proteins/*chemistry Ions Models, Chemical Models, Molecular Models, Secondary Protons Thermodynamics, Statistical Mutation Oxygen/chemistry Protein Structure}, doi = {10.1529/biophysj.106.091934}, author = {Chen, H. and B. Ilan and Y. Wu and Zhu, F. and K. Schulten and G. A. Voth} } @article {705, title = {Charge Delocalization in Proton Channels, II: The Synthetic LS2 Channel and Proton Selectivity}, journal = {Biophys J}, volume = {92}, number = {1}, year = {2007}, note = {Wu, Yujie Ilan, Boaz Voth, Gregory A R01-GM53148/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. United States Biophysical journal Biophys J. 2007 Jan 1;92(1):61-9. Epub 2006 Oct 20.}, pages = {61-9}, abstract = {

In this study, the minimalist synthetic LS2 channel is used as a prototype to examine the selectivity of protons over other cations. The free-energy profiles along the transport pathway of LS2 are calculated for three cation species: a realistic delocalized proton (including Grotthuss shuttling){\textendash}H(+), a classical (nonshuttling) hydronium{\textendash}H(3)O(+), and a potassium cation{\textendash}K(+). The overall barrier for K(+) is approximately twice as large as that for H(+), explaining the \>100 times larger maximal ion conductance for the latter, in qualitative agreement with the experimental result. The profile for the classical hydronium is quantitatively intermediate between those of H(+) and K(+) and qualitatively more similar to that of H(+), for which the locations of the peaks are well correlated with the troughs of the pore radius profile. There is a strong correlation between the free-energy profiles and the very different characteristic hydration structures of the three cation species. This work suggests that the passage of various cations through ion channels cannot always be explained by simple electrostatic desolvation considerations.

}, keywords = {Biophysics/*methods Cations Electric Conductivity Electrons Hydrogen/chemistry Ion Channel Gating Ion Channels/*chemistry Models, Molecular Molecular Conformation Potassium/chemistry Protein Conformation Protons Reproducibility of Results Thermodynamics Water/chemistry}, doi = {10.1529/biophysj.106.091942}, author = {Y. Wu and B. Ilan and G. A. Voth} } @article {659, title = {Proton Solvation and Transport in Aqueous and Biomolecular Systems: Insights from Computer Simulations}, journal = {J Phys Chem B}, volume = {111}, number = {17}, year = {2007}, note = {Swanson, Jessica M J Maupin, C Mark Chen, Hanning Petersen, Matt K Xu, Jiancong Wu, Yujie Voth, Gregory A R01 GM053148-12/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. Review United States The journal of physical chemistry. B J Phys Chem B. 2007 May 3;111(17):4300-14. Epub 2007 Apr 13.}, pages = {4300-14}, abstract = {

The excess proton in aqueous media plays a pivotal role in many fundamental chemical (e.g., acid-base chemistry) and biological (e.g., bioenergetics and enzyme catalysis) processes. Understanding the hydrated proton is, therefore, crucial for chemistry, biology, and materials sciences. Although well studied for over 200 years, excess proton solvation and transport remains to this day mysterious, surprising, and perhaps even misunderstood. In this feature article, various efforts to address this problem through computer modeling and simulation will be described. Applications of computer simulations to a number of important and interesting systems will be presented, highlighting the roles of charge delocalization and Grotthuss shuttling, a phenomenon unique in many ways to the excess proton in water.

}, keywords = {Biological Transport *Computer Simulation *Protons Solubility Solvents/*chemistry Water/chemistry}, doi = {10.1021/jp070104x}, author = {Swanson, J. M. and Maupin, C. M. and Chen, H. and Petersen, M. K. and Xu, J. and Y. Wu and G. A. Voth} } @article {426, title = {Proton Transport Behavior Through the Influenza A M2 Channel: Insights from Molecular Simulation}, journal = {Biophys. J.}, volume = {93}, year = {2007}, pages = {3470-3479}, doi = {10.1529/biophysj.107.105742}, author = {Chen, H. and Y. Wu and G. A. Voth} } @article {706, title = {Flexible Simple Point-charge Water Model with Improved Liquid-State Properties}, journal = {J Chem Phys}, volume = {124}, number = {2}, year = {2006}, note = {Wu, Yujie Tepper, Harald L Voth, Gregory A 1 S10 RR17214-01/RR/NCRR NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov{\textquoteright}t Research Support, U.S. Gov{\textquoteright}t, Non-P.H.S. United States The Journal of chemical physics J Chem Phys. 2006 Jan 14;124(2):024503.}, pages = {024503}, abstract = {

In order to introduce flexibility into the simple point-charge (SPC) water model, the impact of the intramolecular degrees of freedom on liquid properties was systematically studied in this work as a function of many possible parameter sets. It was found that the diffusion constant is extremely sensitive to the equilibrium bond length and that this effect is mainly due to the strength of intermolecular hydrogen bonds. The static dielectric constant was found to be very sensitive to the equilibrium bond angle via the distribution of intermolecular angles in the liquid: A larger bond angle will increase the angle formed by two molecular dipoles, which is particularly significant for the first solvation shell. This result is in agreement with the work of Hochtl et al. [J. Chem. Phys. 109, 4927 (1998)]. A new flexible simple point-charge water model was derived by optimizing bulk diffusion and dielectric constants to the experimental values via the equilibrium bond length and angle. Due to the large sensitivities, the parametrization only slightly perturbs the molecular geometry of the base SPC model. Extensive comparisons of thermodynamic, structural, and kinetic properties indicate that the new model is much improved over the standard SPC model and its overall performance is comparable to or even better than the extended SPC model.

}, keywords = {Algorithms Chemistry, Physical/*methods Computer Simulation Diffusion Electrochemistry/methods Hydrogen/chemistry Hydrogen Bonding Kinetics Models, Statistical Models, Theoretical Molecular Conformation Oxygen/chemistry Thermodynamics Viscosity Water/*chemistry}, doi = {10.1063/1.2136877}, author = {Y. Wu and H. L. Tepper and G. A. Voth} } @article {425, title = {Origins of Proton Transport Behavior from Selectivity Domain Mutations of the Aquaporin-1 Channel}, journal = {Biophys J}, volume = {90}, number = {10}, year = {2006}, note = {Chen, Hanning Wu, Yujie Voth, Gregory A R01-GM53148/GM/NIGMS NIH HHS/United States Letter Research Support, N.I.H., Extramural United States Biophysical journal Biophys J. 2006 May 15;90(10):L73-5. Epub 2006 Mar 31.}, pages = {L73-5}, abstract = {

The permeation free-energy profile and maximum ion conductance of proton transport along the channel of three aquaporin-1 (AQP1) mutants (H180A/R195V, H180A, and R195V) are calculated via molecular dynamics simulations and Poisson-Nernst-Planck theory. The proton dynamics was described by the multistate empirical valence bond (MS-EVB) model. The results reveal three major contributions to the overall free-energy barrier for proton transport in AQP1: 1), the bipolar field, 2), the electrostatic repulsion due to the Arg-195 residue, and 3), the dehydration penalty due to the narrow channel pore. The double mutation (H180A/R195V) drastically drops the overall free-energy barrier by roughly 20 kcal/mol via simultaneously relaxing the direct electrostatic interaction (by R195V) and dehydration effect (by H180A).

}, keywords = {Amino Acid Substitution Aquaporin 1/*chemistry/genetics Cell Membrane/*chemistry Computer Simulation *Ion Channel Gating *Models, Chemical *Models, Molecular Mutagenesis, Site-Directed Porosity Protein Conformation Protein Structure, Tertiary *Protons Structure-Activity Relationship}, doi = {10.1529/biophysj.106.084061}, author = {Chen, H. and Y. Wu and G. A. Voth} } @article {709, title = {A Computational Study of the Closed and Open States of the Influenza A M2 Proton Channel}, journal = {Biophys J}, volume = {89}, number = {4}, year = {2005}, note = {Wu, Yujie Voth, Gregory A GM53148/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, U.S. Gov{\textquoteright}t, P.H.S. United States Biophysical journal Biophys J. 2005 Oct;89(4):2402-11. Epub 2005 Jul 22.}, pages = {2402-11}, abstract = {

In this study, four possible conformations of the His-37 and Trp-41 residues for the closed state of the influenza M2 ion channel were identified by a conformation scan based on a solid-state NMR restraint. In the four conformations, the His-37 residue can be of either the t-160 or t60 rotamer, whereas Trp-41 can be of either the t-105 or t90 rotamer. These conformations were further analyzed by density functional theory calculations and molecular dynamics simulations, and the data indicate that the His-37 residue most likely adopts the t60 rotamer and should be monoprotonated at the delta-nitrogen site, whereas Trp-41 adopts the t90 rotamer. This result is consistent with published experimental data and points to a simple gating mechanism: in the closed state, the His-37 and Trp-41 residues adopt the (t60, t90) conformation, which nearly occludes the pore, preventing nonproton ions from passing through due to the steric and desolvation effects. Moreover, the His-37 tetrad interrupts the otherwise continuous hydrogen-bonding network of the pore water by forcing the water molecules above and below it to adopt opposite orientations, thus adding to the blockage of proton shuttling. The channel can be easily opened by rotating the His-37 chi2 angle from 60 to 0 degrees . This open structure allows pore water to penetrate the constrictive region and to form a continuous water wire for protons to shuttle through, while being still narrow enough to exclude other ions.

}, keywords = {Biological *Models, Chemical *Models, Computer Simulation *Ion Channel Gating Ion Channels/*chemistry Models, Molecular Porosity Protein Conformation Proton Pumps/*chemistry Structure-Activity Relationship Viral Matrix Proteins/*chemistry}, doi = {10.1529/biophysj.105.066647}, author = {Y. Wu and G. A. Voth} } @inbook {744, title = {Computer Simulations of Proton Transport Through the M2 Channel of the Influenza A Virus}, booktitle = {Viral Membrane Proteins: Structure, Function and Drug Design}, year = {2004}, publisher = {Kluwer Academic/Plenum Publishers}, organization = {Kluwer Academic/Plenum Publishers}, chapter = {10}, address = {New York}, author = {Y. Wu and G. A. Voth}, editor = {Fischer, W.} } @article {708, title = {Computational Studies of Proton Transport through the M2 Channel}, journal = {FEBS Lett}, volume = {552}, number = {1}, year = {2003}, note = {Wu, Yujie Voth, Gregory A GM53148/GM/NIGMS NIH HHS/United States Research Support, U.S. Gov{\textquoteright}t, P.H.S. Review Netherlands FEBS letters FEBS Lett. 2003 Sep 18;552(1):23-7.}, pages = {23-7}, abstract = {

The M2 ion channel is an essential component of the influenza A virus. This low-pH gated channel has a high selectivity for protons. Evidence from various experimental data has indicated that the essential structure responsible for the channel is a parallel homo-tetrameric alpha-helix bundle having a left-handed twist with each helix tilted with respect to the membrane normal. A backbone structure has been determined by solid state nuclear magnetic resonance (NMR). Though detailed structures for the side chains are not available yet, evidence has indicated that His37 and Trp41 in the alpha-helix are implicated in the local molecular structure responsible for the selectivity and channel gate. More definitive conformations for the two residues were recently suggested based on the known backbone structure and recently obtained NMR data. While two competitive proton-conductance mechanisms have been proposed, the actual proton-conductance mechanism remains an unsolved problem. Computer simulations of an excess proton in the channel and computational studies of the His37/Trp41 conformations have provided insights into these structural and mechanism issues.

}, keywords = {Computer Simulation DNA/chemistry Histidine/chemistry Hydrogen-Ion Concentration Ions Magnetic Resonance Spectroscopy Models, Molecular Peptides/chemistry Protein Conformation Protein Structure, Secondary *Protons Tryptophan/chemistry Ultraviolet Rays Viral Matrix Proteins/*chemistry/metabolism}, doi = {10.1016/S0014-5793(03)00779-8}, author = {Y. Wu and G. A. Voth} } @article {707, title = {A Computer Simulation Study of the Hydrated Proton in a Synthetic Proton Channel}, journal = {Biophys J}, volume = {85}, number = {2}, year = {2003}, note = {Wu, Yujie Voth, Gregory A GM53148/GM/NIGMS NIH HHS/United States Comparative Study Evaluation Studies Research Support, U.S. Gov{\textquoteright}t, P.H.S. Validation Studies United States Biophysical journal Biophys J. 2003 Aug;85(2):864-75.}, pages = {864-75}, abstract = {

Classical molecular dynamics simulations using the multistate empirical valence bond model for aqueous proton transport were performed to characterize the hydration structure of an excess proton inside a leucine-serine synthetic ion channel, LS2. For such a nonuniform pore size ion channel, it is found that the Zundel ion (H(5)O(2)(+)) solvation structure is generally more stable in narrow channel regions than in wider channel regions, which is in agreement with a recent study on idealized hydrophobic proton channels. However, considerable diversity in the relative stability of the Zundel to Eigen cation (H(9)O(4)(+)) was observed. Three of the five wide channel regions, one located at the channel{\textquoteright}s center and the other two located near the channel mouths, are found to show extraordinary preference for the Eigen solvation structure. This implies that proton hopping is inhibited in these regions and therefore suggests that these regions may behave as barriers in the proton conducting pathway inside the channel. The proton solvation is also greatly influenced by the local molecular environment of the protein. In particular, the polar side chains of the Ser residues, which are intimately involved in the solvation structure, can greatly influence proton solvation. However, no preference of the influence by the various Ser side chains was found; they can either promote or prevent the formation of certain solvation structures.

}, keywords = {Computer Simulation Ion Channel Gating Ion Channels/*chemistry Leucine/*chemistry Membrane Lipids/*chemistry *Models, Molecular Porosity Protein Conformation Proton Pumps/*chemistry *Protons Serine/*chemistry Water/*chemistry}, doi = {10.1016/S0006-3495(03)74526-3}, author = {Y. Wu and G. A. Voth} }