Water molecules at protein–drug interfaces: computational prediction and analysis methods

Samways, Marley L.; Taylor, Richard D.; Macdonald, Hannah E. Bruce; Essex, Jonathan W.

doi:10.1039/d0cs00151a

Cited by 47 publications

(58 citation statements)

References 164 publications

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“…Water networks play an important role in protein-ligand recognition ( 47, 48 ), however their contribution to ligand binding is often difficult to quantify. Here, the combination of ultra-high resolution cryogenic X-ray structures (0.77 and 0.85 Å), a high-resolution room temperature structure (1.1 Å), structures determined using different crystal forms (P4 3 , P2 1 and C2), high resolution neutron structures (1.9 Å and 2.3 Å), and more than 200 fragment bound structures offers an exceptional opportunity to study the role of water in macrodomain structure, function and ligand binding.…”

Section: Resultsmentioning

confidence: 99%

“…Second, the water network analysis identified buried waters that can be targeted for displacement. This strategy is frequently invoked in ligand optimization efforts (48,(61)(62)(63), but it is unclear how broadly applicable this strategy is for optimizing potency. The large number of bridging waters identified here provide an unmatched opportunity to systematically examine the thermodynamics of water displacement (for example, displacement of W17 by the indole-containing ZINC1683100 in Fig.…”

Section: Discussionmentioning

confidence: 99%

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The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and X-ray diffraction at room temperature

Correy

Kneller

Phillips

et al. 2022

Preprint

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The NSP3 macrodomain of SARS CoV 2 (Mac1) removes ADP-ribosylation post-translational modifications, playing a key role in the immune evasion capabilities of the virus responsible for the COVID-19 pandemic. Here, we determined neutron and X-ray crystal structures of the SARS-CoV-2 NSP3 macrodomain using multiple crystal forms, temperatures, and pHs, across the apo and ADP-ribose-bound states. We characterize extensive solvation in the Mac1 active site, and visualize how water networks reorganize upon binding of ADP-ribose and non-native ligands, inspiring strategies for displacing waters to increase potency of Mac1 inhibitors. Determining the precise orientations of active site water molecules and the protonation states of key catalytic site residues by neutron crystallography suggests a catalytic mechanism for coronavirus macrodomains distinct from the substrate-assisted mechanism proposed for human MacroD2. These data provoke a re-evaluation of macrodomain catalytic mechanisms and will guide the optimization of Mac1 inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and X-ray diffraction at room temperature

Correy

Kneller

Phillips

et al. 2022

Preprint

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“… 28 , 29 The idea is that understanding the thermodynamics of active-site water molecules can provide guidance as to whether or not ligand optimization should aim to displace the water, because the energetic cost of displacement would need to be recovered by the ligand–protein interactions. 30 …”

Section: Introductionmentioning

confidence: 99%

Spatially Resolved Hydration Thermodynamics in Biomolecular Systems

Mukherjee

Schäfer

2022

J. Phys. Chem. B

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Water is essential for the structure, dynamics, energetics, and thus the function of biomolecules. It is a formidable challenge to elicit, in microscopic detail, the role of the solvation-related driving forces of biomolecular processes, such as the enthalpy and entropy contributions to the underlying free-energy landscape. In this Perspective, we discuss recent developments and applications of computational methods that provide a spatially resolved map of hydration thermodynamics in biomolecular systems and thus yield atomic-level insights to guide the interpretation of experimental observations. An emphasis is on the challenge of quantifying the hydration entropy, which requires characterization of both the motions of the biomolecules and of the water molecules in their surrounding.

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“…Given the significance of protein-bound water sites (9,10) and the difficulties associated with experimental investigations, a large amount of work has been dedicated to the development of computational methods in this field (11). This has been necessary as conventional molecular dynamics (MD) sampling methods can struggle to sample bound water molecules effectively, especially when the hydration site is buried within a cavity and occluded from bulk solvent (12).…”

Section: Introductionmentioning

confidence: 99%

Enhanced Grand Canonical Sampling of Occluded Water Sites Using Nonequilibrium Candidate Monte Carlo

Melling

Samways

et al. 2022

Preprint

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Water molecules play a key role in biomolecular systems, particularly when bound at protein-ligand interfaces. Simulation studies are hampered by the relatively long timescales on which water exchange between protein and solvent can take place. Grand canonical Monte Carlo (GCMC) is a simulation technique which avoids this issue by attempting the direct insertion and deletion of water molecules. GCMC is, however, hampered by low acceptance probabilities for insertions in congested systems. To address this issue, here, we combine GCMC with nonequilibrium candidate Monte Carlo (NCMC) to yield a new method, grand canonical nonequilibrium candidate Monte Carlo (GCNCMC), in which water insertions and deletions are carried out in a gradual, nonequilibrium fashion. We compare GCNCMC and GCMC simulations of bulk water, and three protein binding sites. We find the efficiency of water sampling is improved by GCNCMC, and that increased sampling of bound ligand conformations is also observed.

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Water molecules at protein–drug interfaces: computational prediction and analysis methods

Abstract: In this review we examine computational approaches to explore the structure and thermodynamics of water binding in protein–drug complexes

Cited by 47 publications

References 164 publications

The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and X-ray diffraction at room temperature

The mechanisms of catalysis and ligand binding for the SARS-CoV-2 NSP3 macrodomain from neutron and X-ray diffraction at room temperature

Spatially Resolved Hydration Thermodynamics in Biomolecular Systems

Enhanced Grand Canonical Sampling of Occluded Water Sites Using Nonequilibrium Candidate Monte Carlo

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