Applications of MMPBSA to Membrane Proteins I: Efficient Numerical Solutions of Periodic Poisson–Boltzmann Equation

Botello‐Smith, Wesley M.; Luo, Ray

doi:10.1021/acs.jcim.5b00341

Cited by 30 publications

(45 citation statements)

References 92 publications

(251 reference statements)

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“…Implementation of an implicit membrane is currently available in packages such as APBS 32 , Delphi 33, 37 , and both the Amber 16 1 and AmberTools 16 2 suites. With the implementation of an implicit membrane model into the Amber/PBSA program 38-42 , the implicit membrane model can be more readily interfaced with the existing MMPBSA framework 3-8 .…”

Section: Introductionmentioning

confidence: 99%

“…Even in its simplified linear form, solving the PBE is a non-trivial endeavor. Due to its complexity, there is no general closed form solution; a numerical solution must be sought with the exception of very simplified geometries 27, 38-40, 42, 48, 59, 60, 84-115 . A semi-analytical Generalized Born (GB) equation was also developed to approximate the PBE solution and is quite popular in biomolecular applications.…”

Section: Introductionmentioning

confidence: 99%

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Modeling Membrane Protein–Ligand Binding Interactions: The Human Purinergic Platelet Receptor

et al. 2016

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Membrane proteins, due to their roles as cell receptors and signaling mediators, make prime candidates for drug targets. The computational analysis of protein-ligand binding affinities has been widely employed as a tool in rational drug design efforts. Although efficient implicit solvent-based methods for modeling globular protein-ligand binding have been around for many years, the extension of such methods to membrane protein-ligand binding is still in its infancy. In this study, we extended the widely used Amber/MMPBSA method to model membrane protein-ligand systems, and we used it to analyze protein-ligand binding for the human purinergic platelet receptor (P2Y12R), a prominent drug target in the inhibition of platelet aggregation for the prevention of myocardial infarction and stroke. The binding affinities, computed by the Amber/MMPBSA method using standard parameters, correlate well with experiment. A detailed investigation of these parameters was conducted to assess their impact on the accuracy of the method. These analyses show the importance of properly treating the non-polar solvation interactions and the electrostatic polarization in the binding of nucleotide agonists and non-nucleotide antagonists to P2Y12R. Based on the crystal structures and the experimental conditions in the binding assay, we further hypothesized that the nucleotide agonists lose their bound magnesium ion upon binding to P2Y12R, and our computational study supports this hypothesis. Ultimately, this work illustrates the value of computational analysis in the interpretation of experimental binding reactions.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modeling Membrane Protein–Ligand Binding Interactions: The Human Purinergic Platelet Receptor

et al. 2016

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“…This labeling scheme has been extended to map all commonly used surfaces, SES, Solvent-Accessible Surface (SAS), van der Waals Surface (VDW), and Density Function Surface (DEN) in recent Amber and AmberTools releases 36, 43, 80, 82, 87, 134, 135 . To minimize the interference to existing procedures and maximize efficiency, a separate integer array is used to label whether a grid point is inside the membrane ( >0) or outside the membrane ( =0).…”

Section: Methodsmentioning

confidence: 99%

“…Numerical solutions are required for biomolecular applications due to their complex shapes 22, 36, 44, 45, 48-87 . Efficient numerical PBE-based solvent models have been widely used to study biological processes including predicting pKa values 88-91 , computing salvation and binding free energies 92-101 , and protein folding 102-112 .…”

Section: Introductionmentioning

confidence: 99%

A Continuum Poisson–Boltzmann Model for Membrane Channel Proteins

Xiao¹,

Diao²,

Greene³

et al. 2017

J. Chem. Theory Comput.

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Membrane proteins constitute a large portion of the human proteome and perform a variety of important functions as membrane receptors, transport proteins, enzymes, signaling proteins, and more. Computational studies of membrane proteins are usually much more complicated than those of globular proteins. Here we propose a new continuum model for Poisson-Boltzmann calculations of membrane channel proteins. Major improvements over the existing continuum slab model are as follows:1) The location and thickness of the slab model are fine-tuned based on explicit-solvent MD simulations. 2) The highly different accessibility in the membrane and water regions are addressed with a two-step, two-probe grid labeling procedure, and 3) The water pores/channels are automatically identified. The new continuum membrane model is optimized (by adjusting the membrane probe, as well as the slab thickness and center) to best reproduce the distributions of buried water molecules in the membrane region as sampled in explicit water simulations. Our optimization also shows that the widely adopted water probe of 1.4 Å for globular proteins is a very reasonable default value for membrane protein simulations. It gives the best compromise in reproducing the explicit water distributions in membrane channel proteins, at least in the water accessible pore/channel regions that we focus on. Finally, we validate the new membrane model by carrying out binding affinity calculations for a potassium channel, and we observe a good agreement with experiment results.

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“…The hydrogen bond is defined when the distance between donor and acceptor atoms less than 3.5 Å and the hydrogen bonding angle larger than 120°. Binding free energies were calculated with the MM/PBSA method (python script) from the Amber 12 package for the equilibrium conformers50515253545556575859. All figures were plotted using OriginPro 9.1.…”

Section: Methodsmentioning

confidence: 99%

Crystal Structure of StnA for the Biosynthesis of Antitumor Drug Streptonigrin Reveals a Unique Substrate Binding Mode

Qian

Zhang

et al. 2017

Sci Rep

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Streptonigrin methylesterase A (StnA) is one of the tailoring enzymes that modify the aminoquinone skeleton in the biosynthesis pathway of Streptomyces species. Although StnA has no significant sequence homology with the reported α/β-fold hydrolases, it shows typical hydrolytic activity in vivo and in vitro. In order to reveal its functional characteristics, the crystal structures of the selenomethionine substituted StnA (SeMet-StnA) and the complex (S185A mutant) with its substrate were resolved to the resolution of 2.71 Å and 2.90 Å, respectively. The overall structure of StnA can be described as an α-helix cap domain on top of a common α/β hydrolase domain. The substrate methyl ester of 10′-demethoxystreptonigrin binds in a hydrophobic pocket that mainly consists of cap domain residues and is close to the catalytic triad Ser185-His349-Asp308. The transition state is stabilized by an oxyanion hole formed by the backbone amides of Ala102 and Leu186. The substrate binding appears to be dominated by interactions with several specific hydrophobic contacts and hydrogen bonds in the cap domain. The molecular dynamics simulation and site-directed mutagenesis confirmed the important roles of the key interacting residues in the cap domain. Structural alignment and phylogenetic tree analysis indicate that StnA represents a new subfamily of lipolytic enzymes with the specific binding pocket located at the cap domain instead of the interface between the two domains.

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Applications of MMPBSA to Membrane Proteins I: Efficient Numerical Solutions of Periodic Poisson–Boltzmann Equation

Cited by 30 publications

References 92 publications

Modeling Membrane Protein–Ligand Binding Interactions: The Human Purinergic Platelet Receptor

Modeling Membrane Protein–Ligand Binding Interactions: The Human Purinergic Platelet Receptor

A Continuum Poisson–Boltzmann Model for Membrane Channel Proteins

Crystal Structure of StnA for the Biosynthesis of Antitumor Drug Streptonigrin Reveals a Unique Substrate Binding Mode

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