GPU-Accelerated Implementation of Continuous Constant pH Molecular Dynamics in Amber: pKa Predictions with Single-pH Simulations

Harris, Robert; Shen, Jana; Huang, Yandong

doi:10.26434/chemrxiv.9642071

Cited by 5 publications

(13 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our analysis revealed that the coupling is communicated through the flexible intersection of TM4 and TM11, whereby changes in the protonation states of Asp133 and Asp163 affect their hydrogen-bonding patterns. Consistent with our previous findings that deprotonated aspartates tend to be stabilized by accepting hydrogen bonds (23,24), the depro- tonated Asp163 is a hydrogen bond acceptor to the sidechain hydroxyl of Thr132 and the backbone amides of Ala131 as well as Thr132 (Fig. 2C).…”

Section: Resultssupporting

confidence: 91%

“…Coupled proton titration is a phenomenon, whereby protonation/deprotonation of two residues affects each other, resulting in irregular titration curves and the necessity to invoke a two-proton model for calculating macroscopic pKas (22). Typically, the coupled residues are hydrogen bonded to each other, such as the aspartyl dyad in enzymes (23,24), or spatially proximal to each other, such as the adjacent Asp407/Asp408 in the E. coli multidrug efflux transporter AcrB, which pumps out one drug molecule for two protons (17). Interestingly, we found that the titration curve of Asp163 in K300A NhaA is irregular (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Alternative proton-binding site and long-distance coupling in Escherichia coli sodium–proton antiporter NhaA

Henderson

Huang

Beckstein

et al. 2020

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

Self Cite

View full text Add to dashboard Cite

Escherichia coli NhaA is a prototypical sodium–proton antiporter responsible for maintaining cellular ion and volume homeostasis by exchanging two protons for one sodium ion; despite two decades of research, the transport mechanism of NhaA remains poorly understood. Recent crystal structure and computational studies suggested Lys300 as a second proton-binding site; however, functional measurements of several K300 mutants demonstrated electrogenic transport, thereby casting doubt on the role of Lys300. To address the controversy, we carried out state-of-the-art continuous constant pH molecular dynamics simulations of NhaA mutants K300A, K300R, K300Q/D163N, and K300Q/D163N/D133A. Simulations suggested that K300 mutants maintain the electrogenic transport by utilizing an alternative proton-binding residue Asp133. Surprisingly, while Asp133 is solely responsible for binding the second proton in K300R, Asp133 and Asp163 jointly bind the second proton in K300A, and Asp133 and Asp164 jointly bind two protons in K300Q/D163N. Intriguingly, the coupling between Asp133 and Asp163 or Asp164 is enabled through the proton-coupled hydrogen-bonding network at the flexible intersection of two disrupted helices. These data resolve the controversy and highlight the intricacy of the compensatory transport mechanism of NhaA mutants. Alternative proton-binding site and proton sharing between distant aspartates may represent important general mechanisms of proton-coupled transport in secondary active transporters.

show abstract

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Alternative proton-binding site and long-distance coupling in Escherichia coli sodium–proton antiporter NhaA

Henderson

Huang

Beckstein

et al. 2020

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…The most recently developed CpH methods enable such calculations with either coarse-grained force fields or full-atom representations using classical or polarized force fields 7-12 . The evaluation of pKa values for all the residues of protein systems of interest remains a computational challenge, however, despite considerable improvements in speed 7, 9 . ECpH lessens this burden somewhat by requiring the knowledge of individual pKa values only for key residues.…”

Section: Discussionmentioning

confidence: 99%

An equilibrium constant pH molecular dynamics method for accurate prediction of pH-dependence in protein systems: Theory and application

Kots

Weinstein

2020

Preprint

View full text Add to dashboard Cite

Computational modeling and simulation of biomolecular systems at their functional pH ranges requires an accurate approach to exploring the pH dependence of conformations and interactions. Here we present a new approach – the Equilibrium Constant pH (ECpH) method – to perform conformational sampling of protein systems in the framework of molecular dynamics simulations in an N, P, T-thermodynamic ensemble. The performance of ECpH is illustrated for two proteins with experimentally determined conformational responses to pH change: the small globular water-soluble bovine b-lactoglobulin (BBL), and the dimer transmembrane antiporter CLC-ec1 Cl−/H+. We show that with computational speeds comparable to equivalent canonical MD simulations we performed, the ECpH trajectories reproduce accurately the pH-dependent conformational changes observed experimentally in these two protein systems, some of which were not seen in the corresponding canonical MD simulations.Abstract FigureTable of Contents artwork

show abstract

“…To counter this, many groups have applied λ-dynamics, based off pioneering work by Brooks et al 20 (in turn based on earlier work with other thermodynamic properties in mind), 21,22 which treats the protonation state of individual amino acid sites as continuous degrees of freedom rather than discrete ones sampled distinctly. [23][24][25] Other efforts focus on enhancing/accelerating conformational sampling through GPU processing 26 or replica exchange. 27,28 Ultimately, regardless of solvation, one struggle for all CpHMD methods is verification of the ensemble of conformational and protonation states they generate, due to paucity of complementary experimental results.…”

Section: Introductionmentioning

confidence: 99%

Titr-DMD – A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework

Reilley

Alexandrova²,

Wang³

et al. 2021

Preprint

View full text Add to dashboard Cite

The pH dependence of enzyme fold stability and catalytic activity is a fundamentally dynamic, structural property which is difficult to study. Computational methods, particularly constant pH molecular dynamics (CpHMD), are the best situated tools for this. However, these often struggle with affordable sampling of sufficiently long timescales, accuracy of pKa prediction, and verification of the structures they generate. We introduce Titr-DMD, an affordable CpHMD method with a protonation state sampler that can be systematically improved, to circumvent these issues. We benchmark the method on a set of proteins with experimentally attested pKa and on the pH triggered conformational change in a staphylococcal nuclease mutant, a rare experimental study of such behavior. Our results show Titr-DMD to be an effective method to study pH coupled protein dynamics. <br>

show abstract

GPU-Accelerated Implementation of Continuous Constant pH Molecular Dynamics in Amber: pKa Predictions with Single-pH Simulations

Abstract: This paper reports a GPU-accelerated implementation and testing data of the generalized Born based continuous constant pH molecular dynamics method in the Amber package.

Cited by 5 publications

References 50 publications

Alternative proton-binding site and long-distance coupling in Escherichia coli sodium–proton antiporter NhaA

Alternative proton-binding site and long-distance coupling in Escherichia coli sodium–proton antiporter NhaA

An equilibrium constant pH molecular dynamics method for accurate prediction of pH-dependence in protein systems: Theory and application

Titr-DMD – A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework

Contact Info

Product

Resources

About