Realistic Simulations of Proton Transport along the Gramicidin Channel:  Demonstrating the Importance of Solvation Effects

Braun‐Sand, Sonja; Burykin, Anton; Chu, Zhen T.; Warshel, Arieh

doi:10.1021/jp0465783

Cited by 64 publications

(89 citation statements)

References 64 publications

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“…However, this idea was brought up in conjunction with the connectivity of EH to unprotonated water molecules. Here, in contrast, we explored the actual PT process, where the energetics of orienting water chains play only a minor part (27). In fact, the role of the conformational change appeared to be associated with minimizing the need for connecting water molecules.…”

Section: Discussion and Analysismentioning

confidence: 99%

Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome c oxidase

Pisliakov

Sharma

Chu

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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123

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Gaining detailed understanding of the energetics of the protonpumping process in cytochrome c oxidase (CcO) is one of the challenges of modern biophysics. Despite promising mechanistic proposals, most works have not related the activation barriers of the different assumed steps to the protein structure, and there has not been a physically consistent model that reproduced the barriers needed to create a working pump. This work reevaluates the activation barriers for the primary proton transfer (PT) steps by calculations that reflect all relevant free energy contributions, including the electrostatic energies of the generated charges, the energies of water insertion, and large structural rearrangements of the donor and acceptor. The calculations have reproduced barriers that account for the directionality and sequence of events in the primary PT in CcO. It has also been found that the PT from Glu-286 (E) to the propionate of heme a3 (Prd) provides a gate for an initial back leakage from the high pH side of the membrane. Interestingly, the rotation of E that brings it closer to Prd appears to provide a way for blocking competing pathways in the primary PT. Our study elucidates and quantifies the nature of the control of the directionality in the primary PT in CcO and provides instructive insight into the role of the water molecules in biological PT, showing that ''bridges'' of several water molecules in hydrophobic regions present a problem (rather than a solution) that is minimized in the primary PT.coupled electron transfer proton transfer ͉ proton pumps ͉ dielectric effects ͉ free energy calculations ͉ pK a in nonpolar regions

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Section: Discussion and Analysismentioning

confidence: 99%

Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome c oxidase

Pisliakov

Sharma

Chu

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

123

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“…,54 This method has previously been successfully applied to a wide range of systems of biological relevance, such as the aquaporin channel, carbonic anhydrase and the bovine pancreatic trypsin inhibitor, to name a few examples. 52,[58][59][60][61] The protein studied here was first explicitly solvated using the surface constrained all atom solvent (SCAAS) model, 54 employing a water grid with a radius of 20 Å around the investigated residue. Long range interactions were treated using the local reaction field (LRF) approach.…”

Section: Methodsmentioning

confidence: 99%

Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Borštnar

Repič

Kamerlin

et al. 2012

J. Chem. Theory Comput.

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Monoamine oxidase (MAO), which exists in two isozymic forms, MAO A and MAO B, is an important flavoenzyme responsible for the metabolism of amine neurotransmitters such as dopamine, serotonin and norepinephrine. Despite extensive research effort, neither the catalytic nor the inhibition mechanisms of MAO have been completely understood. There has also been dispute with regard to the protonation state of the substrate upon entering the active site, as well as the identity of residues that are important for the initial deprotonation of irreversible acetylenic inhibitors, in accordance with the recently proposed mechanism. Therefore, in order to investigate features essential for the modes of action of MAO, we have calculated pK a values of three relevant tyrosine residues in the MAO B active site, with and without dopamine bound as the substrate (as well as the pK a of the dopamine itself in the active site). The calculated pK a values for Tyr188, Tyr398 and Tyr435 in the complex are found to be shifted upwards to 13.0, 13.7 and 14.7, respectively, relative to 10.1 in aqueous solution, ruling out the likelihood that they are viable proton acceptors. The altered tyrosine pK a values could be rationalized as an interplay of two opposing effects: insertion of positively charged bulky dopamine that lowers tyrosine pK a values, and subsequent removal of water molecules from the active site that elevates tyrosine pK a values, in which the latter prevails. Additionally, the pK a value of the bound dopamine (8.8) is practically unchanged compared to the corresponding value in aqueous solution (8.9), as would be expected from a charged amine placed in a hydrophobic active site consisting of aromatic moieties. We also observed potentially favorable cation-π interactions between -NH 3 + group on dopamine and aromatic moieties, which provide stabilizing effect to the charged fragment. Thus, we offer here theoretical evidence that the amine is most likely to be present in the active site in its protonated form, which is similar to the conclusion from experimental studies of MAO A (Jones et al. J. Neural Trans. 2007, 114, 707-712). However, the free energy cost of 3 transferring the proton from the substrate to the bulk solvent is only 1.9 kcal mol -1 , leaving open the possibility that the amine enters the chemical step in its neutral form. In conjunction with additional experimental and computational work, the data presented here should lead towards a deeper understanding of mechanisms of the catalytic activity and irreversible inhibition of MAO B, which can allow for the design of novel and improved MAO B inhibitors.

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“…Now, as discussed in our recent study of the pK a s in Cytocrome C oxidase (34), it is not simple to interpret apparent pK a of pumping processes even when the relevant sites are known. Furthermore, as discussed in our studies of proton conductance in gramicidin (35,36) it is very hard to obtain unique information on the PTR profile using phenomenological fitting. However, combining the valuable experimental information of ref.…”

Section: Discussionmentioning

confidence: 96%

Realistic simulations of the coupling between the protomotive force and the mechanical rotation of the F ₀ -ATPase

Mukherjee

Warshel

2012

Proc. Natl. Acad. Sci. U.S.A.

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The molecular origin of the action of the F 0 proton gradient-driven rotor presents a major puzzle despite significant structural advances. Although important conceptual models have provided guidelines of how such systems should work, it has been challenging to generate a structure-based molecular model using physical principles that will consistently lead to the unidirectional protondriven rotational motion during ATP synthesis. This work uses a coarse-grained (CG) model to simulate the energetics of the F 0 -ATPase system in the combined space defined by the rotational coordinate and the proton transport (PTR) from the periplasmic side (P) to the cytoplasmic side (N). The model establishes the molecular origin of the rotation, showing that this effect is due to asymmetry in the energetics of the proton path rather than only the asymmetry of the interaction of the Asp on the c-ring helices and Arg on the subunit-a. The simulation provides a clear conceptual background for further exploration of the electrostatic basis of proton-driven mechanochemical systems.T he F 0 F 1 -ATPase is a ubiquitous nanomotor in all living cells that generate the ATP molecules essential for maintaining large gamut of cellular functions (1). This system is comprised of two rotary motors; the mechanochemical F 1 -ATPase that synthesizes or hydrolyzes ATP, utilizing the mechanical torque generated from the rotation of the stalk, and the membranebound F 0 -ATPase that drives the mechanical rotation utilizing the ion-motive force established across the membrane. The detailed nature of the conversion and the utility of energy by the F 0 F 1 -ATPase has long been one of the fundamental questions in biology. Significant progress has been achieved in understanding the mechanochemical coupling in the F 1 -ATPase, utilizing information from several high-resolution crystal structures and a wealth of biochemical and single-molecule spectroscopic data (2-6). Recently, the molecular nature of the coupling between chemical and conformational coordinates in the F 1 -ATPase has been elucidated using coarse-grained (CG) theoretical modeling approaches (7). In contrast, the molecular basis of the conversion of the pH gradient across the membrane producing directional rotation of the F 0 -ATPase is less understood, despite significant conceptual progress (3). The problems are partially due to the limited structural information about the complete membranebound F 0 -ATPase complex and also reflects the inherent difficulty in modeling coupled long-range biological processes, such as proton transfer and mechanical rotation.The F 0 motor is consisted of a rotor part, known as the c-ring, connected with the stator subunit-a and dimer subunits-b. The c-ring is a tightly packed ring-like structure composed of several α-helical hairpins whose number varies in different species (3,8). Most of the central part of the c-ring is embedded in the membrane, except for the cytoplasmic loops and the periplasmic termini. Each c-ring helices consists of a highly conserved ...

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Realistic Simulations of Proton Transport along the Gramicidin Channel: Demonstrating the Importance of Solvation Effects

Cited by 64 publications

References 64 publications

Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome c oxidase

Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome c oxidase

Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Realistic simulations of the coupling between the protomotive force and the mechanical rotation of the F ₀ -ATPase

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Realistic Simulations of Proton Transport along the Gramicidin Channel: Demonstrating the Importance of Solvation Effects

Cited by 64 publications

References 64 publications

Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome c oxidase

Electrostatic basis for the unidirectionality of the primary proton transfer in cytochrome c oxidase

Computational Study of the pKaValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Realistic simulations of the coupling between the protomotive force and the mechanical rotation of the F 0 -ATPase

Contact Info

Product

Resources

About

Computational Study of the pK_aValues of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B

Realistic simulations of the coupling between the protomotive force and the mechanical rotation of the F ₀ -ATPase