Thermodynamic Coupling of Protonation and Conformational Equilibria in Proteins: Theory and Simulation

Shi, Chuanyin; Wallace, Jason A.; Shen, Jana

doi:10.1016/j.bpj.2012.02.021

Cited by 47 publications

(84 citation statements)

References 32 publications

(42 reference statements)

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“…31,32 The hybrid-solvent data shows a slope well below one (0.61), indicative of a systematic underestimation of p K a shifts, which is due to the underestimation of desolvation penalty by the GBSW model (”too wet”). 8,9,57 The above-mentioned trend can also be seen from the histogram of p K a deviations, p K a calc - p K a expt (Fig. S6).…”

Section: Resultssupporting

confidence: 56%

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All-Atom Continuous Constant pH Molecular Dynamics With Particle Mesh Ewald and Titratable Water

Huang

Chen

Wallace

et al. 2016

J. Chem. Theory Comput.

119

238

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Development of a pH stat to properly control solution pH in biomolecular simulations has been a long-standing goal in the community. Towards this goal recent years have witnessed the emergence of the so-called constant pH molecular dynamics methods. However, the accuracy and generality of these methods have been hampered by the use of implicit-solvent models or truncation-based electrostatic schemes. Here we report the implementation of the particle mesh Ewald (PME) scheme into the all-atom continuous constant pH molecular dynamics (CpHMD) method, enabling CpHMD to be performed with a standard MD engine at a fractional added computational cost. We demonstrate the performance using pH replica-exchange CpHMD simulations with titratable water for a stringent test set of proteins, HP36, BBL, HEWL and SNase. With the sampling time of 10 ns per replica, most pKa’s are converged, yielding the average absolute and root-mean-square deviations of 0.61 and 0.77, respectively, from experiment. Linear regression of the calculated vs experimental pKa shifts gives a correlation coefficient of 0.79, a slope of 1 and an intercept near 0. Analysis reveals inadequate sampling of structure relaxation accompanying a protonation-state switch as a major source of the remaining errors, which are reduced as simulation prolongs. These data suggest PME-based CpHMD can be used as a general tool for pH-controlled simulations of macromolecular systems in various environments, enabling atomic insights into pH-dependent phenomena involving not only soluble proteins but also transmembrane proteins, nucleic acids, surfactants and polysaccharides.

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Section: Resultssupporting

confidence: 56%

“…Such overshifts are not seen in the hybrid-solvent simulations, which may be in part attributed to the fortuitous cancellation of errors between the underestimation of desolvation by the GBSW model and the overestimation of desolvation resulting from inadequate structural relaxation based on our previous studies of buried residues. 9,57 …”

Section: Resultsmentioning

confidence: 99%

All-Atom Continuous Constant pH Molecular Dynamics With Particle Mesh Ewald and Titratable Water

Huang

Chen

Wallace

et al. 2016

J. Chem. Theory Comput.

119

238

View full text Add to dashboard Cite

show abstract

“…The most widely employed approach regarding these models is the Constant pH Molecular Dynamics (CpHMD) (Bürgi et al, 2002 andMongan et al, 2004), in which the solution pH should be specified as an external variable. One advantage of these CpHMD methods is that they allow the investigation of pH-dependent properties of proteins, and the correlation between protonation and conformational states (Dissanayake et al, 2015;Shi et al, 2012 andZeng et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Unraveling HIV protease flaps dynamics by Constant pH Molecular Dynamics simulations

Soares

Tôrres

Silva

et al. 2016

Journal of Structural Biology

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a b s t r a c tThe active site of HIV protease (HIV-PR) is covered by two flaps. These flaps are known to be essential for the catalytic activity of the HIV-PR, but their exact conformations at the different stages of the enzymatic pathway remain subject to debate. Understanding the correct functional dynamics of the flaps might aid the development of new HIV-PR inhibitors. It is known that, the HIV-PR catalytic efficiency is pHdependent, likely due to the influence of processes such as charge transfer and protonation/deprotonation of ionizable residues. Several Molecular Dynamics (MD) simulations have reported information about the HIV-PR flaps. However, in MD simulations the protonation of a residue is fixed and thus it is not possible to study the correlation between conformation and protonation state. To address this shortcoming, this work attempts to capture, through Constant pH Molecular Dynamics (CpHMD), the conformations of the apo, substrate-bound and inhibitor-bound HIV-PR, which differ drastically in their flap arrangements. The results show that the HIV-PR flaps conformations are defined by the protonation of the catalytic residues Asp25/Asp25 0 and that these residues are sensitive to pH changes. This study suggests that the catalytic aspartates can modulate the opening of the active site and substrate binding.

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“…26 Combined with the pH replica-exchange sampling protocol, 26 it offers accurate p K a convergence on the order of 1 ns per pH replica, 26 in particular for interior sites of proteins that are notoriously challenging to predict with static structure-based electrostatics methods. 27,28 A benchmark study showed that hybrid-solvent CpHMD can predict the p K a ’s of enzyme catalytic sites with a correct order and accuracy of about 1 pH unit. 26 Most recently, we applied hybrid-solvent CpHMD to study the apo form of BACE1, revealing a pH-dependent population shift between three conformational states that gives rise to the bell-shaped pH profile of the enzymatic activity.…”

mentioning

confidence: 99%

Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors

Ellis

Tsai

Hou

et al. 2016

J. Phys. Chem. Lett.

100

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Targeting BACE1 with small-molecule inhibitors offers a promising route for treatment of Alzheimer’s disease. However, the intricate pH dependence of BACE1 function and inhibitor efficacy has posed major challenges for structure-based drug design. Here we investigate two, structurally similar BACE1 inhibitors that have dramatically different binding affinity and inhibitory activity using continuous constant pH molecular dynamics (CpHMD). At high pH, both inhibitors are stably bound to BACE1, however, within the enzyme active pH range, only the iminopyrimidinone-based inhibitor remains bound, while the aminothiazine-based inhibitor becomes partially dissociated following the loss of hydrogen bonding with the active site and change of the 10s loop conformation. The drastically lower affinity of the second inhibitor is due to the protonation of a catalytic aspartate and the lack of a propyne tail. This work demonstrates that CpHMD can be used for screening pH-dependent binding profiles of small-molecule inhibitors, providing a new tool for structure-based drug design and optimization.

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Thermodynamic Coupling of Protonation and Conformational Equilibria in Proteins: Theory and Simulation

Cited by 47 publications

References 32 publications

All-Atom Continuous Constant pH Molecular Dynamics With Particle Mesh Ewald and Titratable Water

All-Atom Continuous Constant pH Molecular Dynamics With Particle Mesh Ewald and Titratable Water

Unraveling HIV protease flaps dynamics by Constant pH Molecular Dynamics simulations

Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors

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