Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Bodnarchuk, Michael S.; Viner, Russell; Michel, Julien; Essex, Jonathan W.

doi:10.1021/ci400674k

Cited by 48 publications

(60 citation statements)

References 65 publications

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“…45,46 Notably, both studies found that Clark's equation only yielded reliable free energies when B was low. This was previously thought to be due to sampling problems.…”

Section: Free Energies Via Titrationmentioning

confidence: 98%

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo

2015

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Water molecules play integral roles in the formation of many protein-ligand complexes, and recent computational efforts have been focused on predicting the thermodynamic properties of individual waters and how they may be exploited in rational drug design. However, when water molecules form highly coupled hydrogen bonding networks, there is, as yet, no method that can rigorously calculate the free energy to bind the entire network, or assess the degree of cooperativity between waters. In this work, we report theoretical and methodological developments to the grand canonical Monte Carlo simulation technique. Central to our results is a rigorous equation that can be used to calculate efficiently the binding free energies of water networks of arbitrary size and complexity. Using a single set of simulations, our methods can locate waters, estimate their binding affinities, capture the cooperativity of the water network, and evaluate the hydration free energy of entire protein binding sites. Our techniques have been applied to multiple test systems and compare favourably to thermodynamic integra- *

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“…45,46 Notably, both studies found that Clark's equation only yielded reliable free energies when B was low. This was previously thought to be due to sampling problems.…”

Section: Free Energies Via Titrationmentioning

confidence: 98%

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo

2015

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“…Moreover, the binding affinity of substrates/inhibitors may diminish if the free energy increases due to the removal of bound water molecules is not compensated by additional interactions upon their binding. 43 These water molecules are essential to represent the electrostatic behaviour of the active site, 24 helping us to answer some of our mechanistic questions. Our Quantum Chemical Cluster Approach calculations support the idea that water molecules change the electrostatic environment of the active site allowing MAO B to catalyse the studied substrates by two different mechanisms.…”

Section: Importance Of Crystallographic Water Moleculesmentioning

confidence: 99%

Revealing Monoamine Oxidase B Catalytic Mechanisms by Means of the Quantum Chemical Cluster Approach

Zapata‐Torres

Fierro

Barriga-González

et al. 2015

J. Chem. Inf. Model.

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Two of the possible catalytic mechanisms for neurotransmitter oxidative deamination by monoamine oxidase B (MAO B), namely, polar nucleophilic and hydride transfer, were addressed in order to comprehend the nature of their rate-determining step. The Quantum Chemical Cluster Approach was used to obtain transition states of MAO B complexed with phenylethylamine (PEA), benzylamine (BA), and p-nitrobenzylamine (NBA). The choice of these amines relies on their importance to address MAO B catalytic mechanisms so as to help us to answer questions such as why BA is a better substrate than NBA or how para-substitution affects substrate's reactivity. Transition states were later validated by comparison with the experimental free energy barriers. From a theoretical point of view, and according to the our reported transition states, their calculated barriers and structural and orbital differences obtained by us among these compounds, we propose that good substrates such as BA and PEA might follow the hydride transfer pathway while poor substrates such as NBA prefer the polar nucleophilic mechanism, which might suggest that MAO B can act by both mechanisms. The low free energy barriers for BA and PEA reflect the preference that MAO B has for hydride transfer over the polar nucleophilic mechanism when catalyzing the oxidative deamination of neurotransmitters.

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“…The method has the advantage of being able to identify preferred water molecule positions and at the same time rigorously calculate binding free energies in a single set of simulations. In addition, the approach naturally takes into account cooperative effects in water networks 20,22,23 . By post-processing the trajectories, it is also possible to rigorously rank order every water molecule or network in the GC region by their binding affinities.…”

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confidence: 99%

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

et al. 2018

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Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.

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Strategies to Calculate Water Binding Free Energies in Protein–Ligand Complexes

Cited by 48 publications

References 65 publications

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo

Water Sites, Networks, And Free Energies with Grand Canonical Monte Carlo

Revealing Monoamine Oxidase B Catalytic Mechanisms by Means of the Quantum Chemical Cluster Approach

Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

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