Computation of p<scp>H</scp>‐dependent binding free energies

Kim, M. Olivia; McCammon, J. Andrew

doi:10.1002/bip.22702

Cited by 26 publications

(21 citation statements)

References 84 publications

(155 reference statements)

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“…In pH-dependent systems, titratable residues are often pointed out as potential molecular switches involved in protein binding and transport 24 , 25 . We investigated the influence of a transmembrane pH gradient on the titration behavior of AdiC (see Material and Methods).…”

Section: Resultsmentioning

confidence: 99%

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Krammer

Gibbons

Roos

et al. 2018

Sci Rep

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The arginine-agmatine antiporter (AdiC) is a component of an acid resistance system developed by enteric bacteria to resist gastric acidity. In order to avoid neutral proton antiport, the monovalent form of arginine, about as abundant as its divalent form under acidic conditions, should be selectively bound by AdiC for transport into the cytosol. In this study, we shed light on the mechanism through which AdiC distinguishes Arg+ from Arg2+ of arginine by investigating the binding of both forms in addition to that of divalent agmatine, using a combination of molecular dynamics simulations with molecular and quantum mechanics calculations. We show that AdiC indeed preferentially binds Arg+. The weaker binding of divalent compounds results mostly from their greater tendency to remain hydrated than Arg+. Our data suggests that the binding of Arg+ promotes the deprotonation of Glu208, a gating residue, which in turn reinforces its interactions with AdiC, leading to longer residence times of Arg+ in the binding site. Although the total electric charge of the ligand appears to be the determinant factor in the discrimination process, two local interactions formed with Trp293, another gating residue of the binding site, also contribute to the selection mechanism: a cation-π interaction with the guanidinium group of Arg+ and an anion-π interaction involving Glu208.

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Section: Resultsmentioning

confidence: 99%

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Krammer

Gibbons

Roos

et al. 2018

Sci Rep

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“…However, it is a known fact that the protonation states of a typical ionisable group involve dynamic processes that can alter the chemical environment during binding. Previous studies [133,134] Constant pH molecular dynamics (or CpHMD), has been developed for the computational prediction of pKa values [135] for ionisable residues in the biological systems under study (refer to Box 2). The early CpHMD approach employed GB solvent as the continuum aqueous environment and Langevin dynamics for the propagation through the non-solvent (or solute) trajectories [136].…”

Section: Constant Ph Molecular Dynamicsmentioning

confidence: 99%

Molecular dynamics-driven drug discovery: leaping forward with confidence

Ganesan

Coote

Barakat

2017

Drug Discovery Today

289

183

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Given the significant time and financial costs of developing a commercial drug, it remains important to constantly reform the drug discovery pipeline with novel technologies that can narrow the candidates down to the most promising lead compounds for clinical testing. The past decade has witnessed tremendous growth in computational capabilities that enable in silico approaches to expedite drug discovery processes. Molecular dynamics (MD) has become a particularly important tool in drug design and discovery. From classical MD methods to more sophisticated hybrid classical/quantum mechanical (QM) approaches, MD simulations are now able to offer extraordinary insights into ligand-receptor interactions. In this review, we discuss how the applications of MD approaches are significantly transforming current drug discovery and development efforts.

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“…Different aspects of available computational methods to study acid-base processes in biomolecules have been reviewed in the literature (Mongan and Case 2005;Chen et al 2008Chen et al , 2014Wallace and Shen 2009;Alexov et al 2011;Kim and McCammon 2016), evidencing their increasingly important role in biophysics, biochemistry, and biotechnological processes. Most of the reviews concentrated their discussions on atomistic level constant-pH (CpH) molecular dynamics (MD) techniques.…”

Section: Introductionmentioning

confidence: 99%

Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems

daSilva

Dias

2017

Biophys Rev

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pH is a critical parameter for biological and technological systems directly related with electrical charges. It can give rise to peculiar electrostatic phenomena, which also makes them more challenging. Due to the quantum nature of the process, involving the forming and breaking of chemical bonds, quantum methods should ideally by employed. Nevertheless, due to the very large number of ionizable sites, different macromolecular conformations, salt conditions, and all other charged species, the CPU time cost simply becomes prohibitive for computer simulations, making this a quite complex problem. Simplified methods based on Monte Carlo sampling have been devised and will be reviewed here, highlighting the updated state-ofthe-art of this field, advantages, and limitations of different theoretical protocols for biomolecular systems (proteins and nucleic acids). Following a historical perspective, the discussion will be associated with the applications to protein interactions with other proteins, polyelectrolytes, and nanoparticles.

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Computation of pH‐dependent binding free energies

Cited by 26 publications

References 84 publications

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC

Molecular dynamics-driven drug discovery: leaping forward with confidence

Development of constant-pH simulation methods in implicit solvent and applications in biomolecular systems

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