Analysis of the influence of simulation parameters on biomolecule-linked water networks

Jeszenői, Norbert; Schilli, Gabriella; Bálint, Mónika; Horváth, István; Hetényi, Csaba

doi:10.1016/j.jmgm.2018.04.011

Cited by 3 publications

(1 citation statement)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They can form a hydration shell [16] that is either conserved or displaced upon ligand binding. If hydration shell water molecules are conserved upon ligand binding, they turn into bridges forming a static network of solute-water and water-water hydrogen bonds [13,15,[17][18][19][20][21][22][23][24]. Such a static network is characterized by a low mobility and acts by stabilizing complexes.…”

Section: Introductionmentioning

confidence: 99%

The Advances and Limitations of the Determination and Applications of Water Structure in Molecular Engineering

Zsidó

Bayarsaikhan

Börzsei

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

Water is a key actor of various processes of nature and, therefore, molecular engineering has to take the structural and energetic consequences of hydration into account. While the present review focuses on the target–ligand interactions in drug design, with a focus on biomolecules, these methods and applications can be easily adapted to other fields of the molecular engineering of molecular complexes, including solid hydrates. The review starts with the problems and solutions of the determination of water structures. The experimental approaches and theoretical calculations are summarized, including conceptual classifications. The implementations and applications of water models are featured for the calculation of the binding thermodynamics and computational ligand docking. It is concluded that theoretical approaches not only reproduce or complete experimental water structures, but also provide key information on the contribution of individual water molecules and are indispensable tools in molecular engineering.

show abstract

Section: Introductionmentioning

confidence: 99%

The Advances and Limitations of the Determination and Applications of Water Structure in Molecular Engineering

Zsidó

Bayarsaikhan

Börzsei

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

The role of water in ligand binding

Zsidó

Hetényi

2021

Current Opinion in Structural Biology

View full text Add to dashboard Cite

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

Szalai,

Bajusz,

Börzsei

et al. 2024

J. Chem. Inf. Model.

View full text Add to dashboard Cite

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 (H 2 O) to heavy water (D 2 O) 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 confirmed the importance of considering binding site water networks in computational ligand design.

show abstract

Analysis of the influence of simulation parameters on biomolecule-linked water networks

Cited by 3 publications

References 91 publications

The Advances and Limitations of the Determination and Applications of Water Structure in Molecular Engineering

The Advances and Limitations of the Determination and Applications of Water Structure in Molecular Engineering

The role of water in ligand binding

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

Contact Info

Product

Resources

About