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primary topic: Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments

Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments
type: AcademicArticle
type: Article
abstract: Rational drug design focuses on the explanation and prediction of complex formation between therapeutic targets and small-molecule ligands. As a third and often overlooked interacting partner, water molecules play a critical role in the thermodynamics of protein−ligand binding, impacting both the entropy and enthalpy components of the binding free energy and by extension, on-target affinity and bioactivity. The community has realized the importance of binding site waters, as evidenced by the number of computational tools to predict the structure and thermodynamics of their networks. However, quantitative experimental characterization of relevant protein−ligand−water systems, and consequently the validation of these modeling methods, remains challenging. Here, we investigated the impact of solvent exchange from light (H2O) to heavy water (D2O) to provide complete thermodynamic profiling of these ternary systems. Utilizing the solvent isotope effects, we gain a deeper understanding of the energetic contributions of various components. Specifically, we conducted isothermal titration calorimetry experiments on trypsin with a series of psubstituted benzamidines, as well as carbonic anhydrase II (CAII) with a series of aromatic sulfonamides. Significant differences in binding enthalpies found between light vs heavy water indicate a substantial role of the binding site water network in protein−ligand binding. Next, we challenged two conceptually distinct modeling methods, the grid-based WaterFLAP and the molecular dynamicsbased MobyWat, by predicting and scoring relevant water networks. The predicted water positions accurately reproduce those in available high-resolution X-ray and neutron diffraction structures of the relevant protein−ligand complexes. Estimated energetic contributions of the identified water networks were corroborated by the experimental thermodynamics data. Besides providing a direct validation for the predictive power of these methods, our findings conf…
date: 2024
volume: 64
issue: 23
is part of: JOURNAL OF CHEMICAL INFORMATION AND MODELING
status: peerReviewed
status: published
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository
has document: Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Text)
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subject: QD Chemistry / kémia

Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Text)
type: Document
license: http://creativecommons.org/licenses/by/3.0/
has file: szalai2024.pdf
has part: szalai2024.pdf

JOURNAL OF CHEMICAL INFORMATION AND MODELING
type: Collection
issn: 15499596

Janez Ilaš
type: Person
given name: Janez
family name: Ilaš

Rita Börzsei
type: Person
given name: Rita
family name: Börzsei

Dávid Bajusz
type: Person
given name: Dávid
family name: Bajusz

Balázs Zoltán Zsidó
type: Person
given name: Balázs Zoltán
family name: Zsidó

György Ferenczy
type: Person
given name: György
family name: Ferenczy

György Miklós Keserű
type: Person
given name: György Miklós
family name: Keserű

Csaba Hetényi
type: Person
given name: Csaba
family name: Hetényi

Tibor Viktor Szalai
type: Person
given name: Tibor Viktor
family name: Szalai

Gyógyszerkémiai Kutatócsoport HRN TTK / SZKI GyKKCs [2014-]
type: Organization

Farmakológiai és Farmakoterápiai Intézet PTE / ÁOK FFI
type: Organization

Szerves Kémia és Technológia Tanszék BME / VBK SZKTT [2006-]
type: Organization

Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)
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Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)
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Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)
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Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments (Other)
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primary topic: Effect of Water Networks On Ligand Binding: Computational Predictions vs Experiments

QD Chemistry / kémia
type: Concept