Advances in the Treatment of Explicit Water Molecules in Docking and Binding Free Energy Calculations

Hu, Xiao; Maffucci, Irene; Contini, Alessandro

doi:10.2174/0929867325666180514110824

Cited by 16 publications

(21 citation statements)

References 240 publications

(293 reference statements)

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“…Thus, the abundant possibilities in the water arrangement prohibit a feasible, explicit evaluation of all the potential water interactions. The current state of how the water can be treated explicitly in docking is reviewed in [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Binding Affinity via Docking: Fact and Fiction

2018

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In 1982, Kuntz et al. published an article with the title “A Geometric Approach to Macromolecule-Ligand Interactions”, where they described a method “to explore geometrically feasible alignment of ligands and receptors of known structure”. Since then, small molecule docking has been employed as a fast way to estimate the binding pose of a given compound within a specific target protein and also to predict binding affinity. Remarkably, the first docking method suggested by Kuntz and colleagues aimed to predict binding poses but very little was specified about binding affinity. This raises the question as to whether docking is the right tool to estimate binding affinity. The short answer is no, and this has been concluded in several comprehensive analyses. However, in this opinion paper we discuss several critical aspects that need to be reconsidered before a reliable binding affinity prediction through docking is realistic. These are not the only issues that need to be considered, but they are perhaps the most critical ones. We also consider that in spite of the huge efforts to enhance scoring functions, the accuracy of binding affinity predictions is perhaps only as good as it was 10–20 years ago. There are several underlying reasons for this poor performance and these are analyzed. In particular, we focus on the role of the solvent (water), the poor description of H-bonding and the lack of the systems’ true dynamics. We hope to provide readers with potential insights and tools to overcome the challenging issues related to binding affinity prediction via docking.

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Section: Introductionmentioning

confidence: 99%

Binding Affinity via Docking: Fact and Fiction

2018

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“…The contribution from each residue of the TDP‐43 protein to the binding energy was calculated using molecular mechanics/generalized Born surface area (MM‐GBSA) decomposition protocol within the MMPBSA.py module 40–44 . The reason for choosing MM‐GBSA to decompose energy is because it saves time than MM‐PBSA 44 .…”

Section: Methodsmentioning

confidence: 99%

“…The contribution from each residue of the TDP-43 protein to the binding energy was calculated using molecular mechanics/generalized Born surface area (MM-GBSA) decomposition protocol within the MMPBSA.py module. [40][41][42][43][44] The reason for choosing MM-GBSA to decompose energy is because it saves time than MM-PBSA. 44 For the decompositions of MM-GBSA free energy calculations, the total binding free energy of each residue was decomposed into four contributions from the individual residue-residue pairs, including van der Waals interaction (E vdw ), electrostatic interaction (E ele ), polar solvation free energy (G pb ) and non-polar solvation free energy (G np ), respectively:…”

Section: Binding Free Energy Calculationmentioning

confidence: 99%

“…The binding mechanism of TDP-43-ssRNA and the identification of key amino acid residuesThe MM-GBSA method was used to decompose the total binding free energy to identify and characterize the detailed interaction of each residue between ssRNA and TDP-43 protein. Explore which residues play major roles in reducing the binding free energy of the studied mutations, and reveal the contribution of key residues in terms of energy.…”

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confidence: 99%

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Exploring the molecular basis of UG‐rich RNA recognition by the human splicing factor TDP‐43 using molecular dynamics simulation and free energy calculation

Sun

Chen

et al. 2021

J Comput Chem

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Transactivation response element RNA/DNA-binding protein 43 (TDP-43) is involved in the regulation of alternative splicing of human neurodegenerative disease-related genes through binding to long UG-rich RNA sequences. Mutations in TDP-43, most in the homeodomain, cause neurological disorders such as amyotrophic lateral sclerosis and fronto temporal lobar degeneration. Several mutants destabilize the structure and disrupt RNA-binding activity. The biological functions of these mutants have been characterized, but the structural basis behind the loss of RNA-binding activity is unclear. Focused on the specific TDP-43-ssRNA complex (PDB code 4BS2), we applied molecular dynamics simulations and the molecular mechanics Poisson-Boltzmann surface area free energy calculation to characterize and explore the structural and dynamic effects between ssRNA and TDP-43. The energetic analysis indicated that the intermolecular van der Waals interaction and nonpolar solvation energy play an important role in the binding process of TDP-43 and ssRNA.Compared with the wild-type TDP-43, the reduction of the polar or non-polar interaction between all the mutants F149A, D105A/S254A, R171A/D174A, F147L/F149L/ F229L/F231L and ssRNA is the main reason for the reduction of its binding free energy.Decomposing energies suggested that the extensive interactions between TDP-43 and the nitrogenous bases of ssRNA are responsible for the specific ssRNA recognition by TDP-43. These results elucidated the TDP-43-ssRNA interaction comprehensively and further extended our understanding of the previous experimental data. The uncovering of TDP-43-ssRNA recognition mechanism will provide us useful insights and new chances for the development of anti-neurodegenerative drugs.

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“…Docking protocols have been developed to account for water molecules during ligand pose and affinity prediction, with mixed degrees of success, and these methods also inherit the difficulties and limitations typically associated with docking. 85 Many other methods have also been applied prospectively in live drug design, 20,41,165,166 though it is difficult to determine the contribution of the water analysis method to the design strategy, and it has been suggested that many compound modifications suggested would likely have been proposed by medicinal chemists using other structure-based design techniques. 41 It is important that more diverse methods are developed with the aim of forming more direct links between water molecules and ligand structureactivity relationships, to maximise utility in drug discovery and compound development.…”

Section: Application To Compound Designmentioning

confidence: 99%