Water and Aqueous Systems
It is known that water plays a central role in biological and chemical, especially acid-base, processes. Equally important to our understanding of the structure and dynamics of water is understanding the role it plays as a solvent facilitating long-ranged charge transport of species such as ions, excess protons and hydroxide ions. The excess proton and hydroxide ion, both particularly important in acid-base chemistry and biomolecular function, introduce unique challenges to modeling and simulation due to the molecular mechanism by which they effectively hop between water molecules and other ionizable species. This hopping mechanism by which water molecules and ions switch identities without significant molecular rearrangement, termed Grotthuss shuttling, occurs over multiple timescales and requires a simulation methodology that is capable of dynamically adjusting the chemical bonding topology as the excess or depleted proton traverses a constantly rearranging environment of solvating molecules.
Ab initio simulations, which explicitly account for electronic degrees of freedom and naturally account for the evolving rearrangement of chemical bonds, are generally limited to small representative systems short timescales, or extremely approximate levels of ab initio theory due to their computational expense. A class of alternative methods that have proven particularly useful in modeling these complex chemical processes are the multiconfiguration (or multistate) reactive molecular dynamics (MRMD) algorithms. In these methods, the system is described as a linear combination of chemical bond topologies (states), the weights of which evolve over the course of a simulation in response to the changing environment. While such methods are generally applicable to any chemical reactions, our group has developed MRMD for the simulaiton of solvated hydronium and hydroxide ions. We have shown that these multistate reactive models can be parameterized directly from assessable condensed phase ab initio simulations, resulting in models that reproduce the thermodynamic and dynamic properties of the original simulations at a fraction of the computational cost. Recent developments in force-matching algorithms have even been able to reduce, if not completely eliminate, the empiricism of reactive models by describing all effective interactions with flexible tabulated potentials. By first validating the results from these models against current state-of-the-art ab initio simulation methodologies, the molecular mechanisms of important processes in complex condensed phase environments can be investigated at time and length scales beyond the current capabilities of the high-level reference calculations.
In order to study concentrated acidic and basic solutions with multiple protons and hydroxide ions, one can generalize the reactive multistate algorithm in a straightforward manner. This, however, proves to be prohibitively expensive due to the large number of states that need to be included. Instead, a self-consistent iterative scheme has been developed that allows for a computationally tractable simulation of multiple reactive species simultaneously undergoing chemical transformations. The combination of this flexible reactive multistate simulation methodology and reactive models constructed directly from condensed phase ab initio simulations enables the efficient simulation of chemical processes that require multiple time and length scales for a proper description. The solvation structure and transport of excess protons and hydroxide ions is currently under investigation by our group in a number of aqueous systems including bulk water and the air-water interface.
- Knight C, Voth GA. The Curious Case of the Hydrated Proton. Acc. Chem. Res. 2012;45:101-109.
- Xu J, Zhang Y, Voth GA. Infrared Spectrum of the Hydrated Proton in Water. J. Phys. Chem. Lett2011;2:81-86.
- Chen H, Voth GA. The Kinetics of Proton Migration in Liquid Water. J. Phys. Chem. B 2010;114:333–339.
- Xu J, Izvekov S, Voth GA. Structure and Dynamics of Concentrated Hydrochloric Acid Solutions. J. Phys. Chem. B 2010;114:9555–9562.
- Paesani F, Voth GA. The Properties of Water: Insights from Quantum Simulations. J. Phys. Chem. B 2009;113:5702–5719.
- Markovitch O, Chen H, Izvekov S, Paesani F, Voth GA, Agmon N. Special Pair Dance and Partner Selection: Elementary Steps in Proton Transport in Liquid Water. J. Phys. Chem. B 2008;112:9456-9466.
- Petersen MK, Iyengar SS, Day TJF, Voth GA. The Hydrated Proton at the Water Liquid/Vapor Interface. J. Phys. Chem. B 2004;108:14804-14806.
- Biswas R, Tse Y-LS, Tokmakoff A, Voth GA. Role of Pre-Solvation and Anharmonicity in Aqueous Phase Hydrated Proton Solvation and Transport. J. Phys. Chem. B . 2016 ;120(8):1793–1804.
- Tse Y-LS, Knight C, Voth GA. An Analysis of Hydrated Proton Diffusion in Ab Initio Molecular Dynamics. J. Chem. Phys. 2015 ;142(014104):1-13.
- Peng Y, Swanson JMJ, Kang S, Zhou R, Voth GA. Hydrated Excess Protons Can Create Their Own Water Wires. J. Phys. Chem. B. 2015 ;(119).
- Tse Y-LS, Chen C, Lindberg GE, Kumar R, Voth GA. Propensity of Hydrated Excess Protons and Hydroxide Anions for the Air-Water Interface. J. Am. Chem. Soc. 2015 ;137(39):12610-12616.
Proton transport plays a pivotal role in biological systems. From modulating biomolecular interactions to establishing transmembrane electrochemical gradients, protons are a ubiquitous currency for biological transformation. The Voth Group has studied proton transport in biological systems, including channels, tranporters, enzymes, and proton pumps, with the reactive simulation methods described above for well over a decade.
In these studies mechanistic insights have been revealed by analyzing the reaction pathways of proton transport, the corresponding fee energy surfaces, and the role of solvation and protein dynamics. Several important conclusions can be drawn from these previous studies: (1) proton transport occurs through a highly dynamic network of water and ionizable residues that is substantially different from that seen prior to proton diffusion; (2) protonatable amino acids can play a range of roles in proton diffusion from direct ionization to partial charge delocalization to simply controlling solvent dynamics; (3) mechanisms revealed by free energy surfaces can be drastically different from those suggested by minimum energy potential energy pathways (ie, entropy is crucial); and (4) amino acids display interesting trends across biological systems.
Current projects in the Voth Group include:
Cytochrome c Oxidase
Cytochrome c oxidase (CcO) is the fourth complex in the mitochondrial electron transport chain and is one of three types of proton pumps that function in cellular respiration. It catalyzes the reduction of O2 into H2O and uses the released energy to pump protons from the negative inside (N-side) of the membrane to the positive outside (P-side). CcO transports electrons from cytochrome c (on the P-side of the membrane) to its active site (where O2 reduction occurs) through multiple metal centers: the copper cluster (CuA), heme a, and the binuclear center (BNC), which consists of heme a3 and another copper site (CuB). Different redox states of the metal centers formed by electron transfer provide the driving force for proton pumping. In each catalytic cycle, four “chemical” protons are transported from the N-side of the membrane to the active site to form H2O, and another four “pumped” protons are transferred from the N-side to the P-side of the membrane. Two questions have been extensively addressed and studied in the CcO catalytic cycle. One is how proton pumping is coupled to redox state transitions, while the other is how the two proton transport processes are regulated. Understanding the energetics, dynamics, and resulting kinetics of the proton transport in CcO is the key to answering these questions." --- Y. Peng & G. A. Voth Biochimica et Biophysica Acta (BBA) - Bioenergetics, 1817, 518-525
This document is created to track the background, progress and communications of the research project - Proton Transport in Cytochrome c Oxidase. It has been supported by NIH funds (grant No. GM53148) under the major allocation "Charge Transport" in Voth group. The initialization of this project can be tracked down to the year 2005 by the former student Jiancong Xu in Voth Group ( J. Xu, G.A. Voth, Computer simulation of explicit proton translocation in cytochrome c oxidase: the D-pathway, P Natl Acad Sci USA, 102, 6795-6800).
Aquaporin-1 is a fascinating transmembrane protein that facilitates rapid water exchange across the membranes but blocks the diffusion of all cations, including protons. The mechanism by which it does this has been studied by many groups. Simulations from the Voth Group revealed that the transport of excess protons is blocked by a combination of a strong bipolar field created by two macrodipole-containing helices, direct electrostatic interaction with certain amino acids residues (particularly in the NPA region) and a dehydration penalty for a cation entering the selectivity filter. Further simulations have explained changes in these properties due to point mutation, and even predicted a mutation (the R195S AQP-1 mutant) that would transform Aquaporins from proton-blocking to proton-selective-conducting channels. This prediction was later confirmed by experiment.
Influenza A M2 Channel
The influenza A M2 channel is a low-pH activated transmembrane protein that plays a crucial role in the viral life cycle by transporting protons across the viral capsid to acidify the virion and initiate uncoating of the viral nucleic acids. Simulations in the Voth Group have shown the influence of the environmental proton concentration on the channel conformation. Future investigations aim to characterize the His37 associated proton permeation mechanism.
Many enzymes catalyze proton transfer reactions yet few are as fast as carbonic anhydrase (CA), which catalyzes the interconversion of carbon dioxide to bicarbonate and an excess proton at a rate near the diffusion controlled limit. CA enzymes are fundamental to CO2 transport, gluconeogenesis, uriogenesis, and bicarbonate buffering. Thus, inhibitors of CA have a wide range of medical uses from the treatment of glaucoma to acting as a diuretic for the treatment of congestive heart failure.
The rate-limiting step in HCA II's effcient catalysis is the proton transfer between the zinc bound water/hydroxide and HIS-64, which are connected through an intramolecular water wire spanning 8-10 angstroms. The proton transfer event in HCA II is unique in that it represents the boundary between proton "transfer", in which the proton exchanges between a single donor and acceptor group, and proton "transport", in which the proton is transferred through several water molecules via Grotthuss shuttling.
Simulations in the Voth Group have provided free energy profiles for proton transport through CAs, revealing mechanistic insight and explaining, aspects of human carbonic anhydrase's (HCAII) ineresting chemical and self rescue behavior. They have additionally explained the structural origins of the enhanced proton transport behavior of the Y7F mutant (subsequently confirmed experimentally), and the decreased proton tranport of N67 (due to perturbed active site solvation).
Future work aims to characterize the coupled protein and solvent dynamics that enable rapid proton transport between the zinc-bound water and H64, explore self-rescue in new mutants of HCAII mutant, and probe the applicability of Marcus theory to proton transport in HCAII.
Other biomolecules for proton transport
- Xu J, Voth GA. Free Energy Profiles for H+ Conduction in the D-pathway of Cytochrome c Oxidase: A Study of the Wild Type and N98D Mutant Enzymes. Biochim Biophys Acta. 2006 ;1757:852-9.
- Xu J, Sharpe MA, Qin L, Ferguson-Miller S, Voth GA. Storage of an Excess Proton in the Hydrogen-bonded Network of the D-pathway of Cytochrome c Oxidase: Identification of a Protonated Water Cluster. J Am Chem Soc [Internet]. 2007 ;129:2910-3.
- Yamashita T, Voth GA. Insights into the Mechanism of Proton Transport in Cytochrome c Oxidase. J. Am. Chem. Soc. 2011 ;134(2):1147–1152.
- Peng Y, Voth GA. Expanding the View of Proton Pumping in Cytochrome c Oxidase through Computer Simulation. Biochim. et Biophys. Acta-Bioenergetics. 2012 ;1817:518-525.
- Liang R, Swanson JMJ, Voth GA. Benchmark Study of the SCC-DFTB Approach for a Biomolecular Proton Channel. J. Chem. Theor. Comp. 2014 ;10(1):451–462.
- Liang R, Swanson JMJ, Peng Y, Nelson JG, Wikström M, Voth GA. Multiscale Simulations Reveal Key Features of the Proton Pumping Mechanism in Cytochrome c Oxidase. Proc. Nat. Acad. Sci. USA. 2016 ;(113):7420-7425.
- Lee S, Swanson JMJ, Voth GA. Multiscale Simulations Reveal the Proton Transport Mechanism in the ClC-ec1 Antiporter. Biophys. J. 2016 ;110(6):1334–1345.
- Lee S, Liang R, Voth GA, Swason JMJ. Computationally Efficient Multiscale Reactive Molecular Dynamics to Describe Amino Acid Deprotonation in Proteins. J. Chem. Theory Comp. . 2016 ;12:879-891.
- Taraphder S, Maupin CM, Swanson JMJ, Voth GA. Coupling Protein Dynamics with Proton Transport in Human Carbonic Anhydrase II. J. Phys. Chem. B. In Press.