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

Zsidó, Balázs Zoltán; Bayarsaikhan, Bayartsetseg; Börzsei, Rita; Szél, Viktor; Mohos, Violetta; Hetényi, Csaba

doi:10.3390/ijms241411784

Cited by 7 publications

(5 citation statements)

References 193 publications

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“…Water molecules in the interface of the binding partners can form adhesive hydrogen-bonded networks between the partners, stabilizing the protein–ligand complex structure [ 39 , 131 ]. However, accurately assigning all water positions in experimental structures determined by X-ray crystallography is challenging due to its limitations often rooted in the inherent mobility of water [ 132 , 133 ]. Other experimental methods also often suffer from improper or complete lack of water positions [ 133 , 134 , 135 , 136 ], necessitating the use of theoretical methods.…”

Section: Resultsmentioning

confidence: 99%

“…However, accurately assigning all water positions in experimental structures determined by X-ray crystallography is challenging due to its limitations often rooted in the inherent mobility of water [ 132 , 133 ]. Other experimental methods also often suffer from improper or complete lack of water positions [ 133 , 134 , 135 , 136 ], necessitating the use of theoretical methods. Computational studies commonly use MD simulations with explicit solvent models to investigate the above-mentioned roles of water at the atomic level [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

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Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols

Bayarsaikhan,

Zsidó,

Börzsei

et al. 2024

IJMS

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Histones are keys to many epigenetic events and their complexes have therapeutic and diagnostic importance. The determination of the structures of histone complexes is fundamental in the design of new drugs. Computational molecular docking is widely used for the prediction of target–ligand complexes. Large, linear peptides like the tail regions of histones are challenging ligands for docking due to their large conformational flexibility, extensive hydration, and weak interactions with the shallow binding pockets of their reader proteins. Thus, fast docking methods often fail to produce complex structures of such peptide ligands at a level appropriate for drug design. To address this challenge, and improve the structural quality of the docked complexes, post-docking refinement has been applied using various molecular dynamics (MD) approaches. However, a final consensus has not been reached on the desired MD refinement protocol. In this present study, MD refinement strategies were systematically explored on a set of problematic complexes of histone peptide ligands with relatively large errors in their docked geometries. Six protocols were compared that differ in their MD simulation parameters. In all cases, pre-MD hydration of the complex interface regions was applied to avoid the unwanted presence of empty cavities. The best-performing protocol achieved a median of 32% improvement over the docked structures in terms of the change in root mean squared deviations from the experimental references. The influence of structural factors and explicit hydration on the performance of post-docking MD refinements are also discussed to help with their implementation in future methods and applications.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols

Bayarsaikhan,

Zsidó,

Börzsei

et al. 2024

IJMS

Self Cite

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“…They consider issues such as the selection or prediction of hydration sites before starting the simulation, the computational methods that can best predict water positions, the ensuing incorporation of explicit water molecules into the docking procedure, and the methods adopted by various software packages [317]. Several works provide information about the development of specific approaches to the identification of the physically ideal positions for explicit water molecules in a simulation and their utilisation in computational software [294,316,[318][319][320][321][322][323][324][325][326].…”

Section: Solvent Roles In Protein-dna Interactionsmentioning

confidence: 99%

The Study of Molecules and Processes in Solution: An Overview of Questions, Approaches and Applications

Tshilande,

Mammino,

Bilonda

2024

Computation

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Many industrial processes, several natural processes involving non-living matter, and all the processes occurring within living organisms take place in solution. This means that the molecules playing active roles in the processes are present within another medium, called solvent. The solute molecules are surrounded by solvent molecules and interact with them. Understanding the nature and strength of these interactions, and the way in which they modify the properties of the solute molecules, is important for a better understanding of the chemical processes occurring in solution, including possible roles of the solvent in those processes. Computational studies can provide a wealth of information on solute–solvent interactions and their effects. Two major models have been developed to this purpose: a model viewing the solvent as a polarisable continuum surrounding the solute molecule, and a model considering a certain number of explicit solvent molecules around a solute molecule. Each of them has its advantages and challenges, and one selects the model that is more suitable for the type of information desired for the specific system under consideration. These studies are important in many areas of chemistry research, from the investigation of the processes occurring within a living organism to drug design and to the design of environmentally benign solvents meant to replace less benign ones in the chemical industry, as envisaged by the green chemistry principles. The paper presents a quick overview of the modelling approaches and an overview of concrete studies, with reference to selected crucial investigation themes.

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“…Despite the recognized importance of explicit solvent in docking, incorporating water molecules into the docking process presents significant challenges. The large, solvent-accessible interface of macromolecules makes it extremely challenging to accurately model the effects of water molecules within a reasonable computational timeframe [24]. It is worth noting that even the water model used can affect the calculated parameters in the simulations [25,26].…”

Section: Incorporation Of Solventmentioning

confidence: 99%

Molecular Docking in Drug Discovery: Techniques, Applications, and Advancements

Aguiar,

Camps

2024

Preprint

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Objective: The primary objective of this study is to conduct a comprehensive review of the significance of molecular docking in the field of drug discovery. This includes an examination of the various approaches and methods used in molecular docking, as well as an exploration of the techniques used for interpreting and validating docking results. Methods: To gather relevant data, a systematic search was conducted using Web of Science, PubMed, and Google Scholar. The search focused on articles related to molecular docking methodologies and their applications in drug discovery. Additionally, alternative techniques that can be used for more precise simulations of ligand-protein interactions were also considered. Results: Molecular docking has proven to be an incredibly rich and valuable process in the field of drug discovery. Its flexibility allows for the incorporation of advanced computational techniques, thereby enhancing the reliability and efficiency of drug discovery processes. The results of the study highlight the significant strides made in the field of molecular docking, demonstrating its potential to revolutionize drug discovery. Conclusions: Molecular docking continues to evolve, with new advancements being made regularly. Despite the challenges faced, these advancements have significantly contributed to the enhancement of molecular docking, solidifying its position as a crucial tool in the field of drug discovery.

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

Cited by 7 publications

References 193 publications

Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols

Efficient Refinement of Complex Structures of Flexible Histone Peptides Using Post-Docking Molecular Dynamics Protocols

The Study of Molecules and Processes in Solution: An Overview of Questions, Approaches and Applications

Molecular Docking in Drug Discovery: Techniques, Applications, and Advancements

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