Predicting Positions of Bridging Water Molecules in Nucleic Acid–Ligand Complexes

Abstract

Over the past two decades, interests in DNA and RNA as drug targets have been growing rapidly. Following the trends observed with protein drug targets, computational approaches for drug design have been developed for this new class of molecules. Our efforts toward the development of a universal docking program, FITTED, led us to focus on nucleic acids. Throughout the development of this docking program, efforts were directed toward displaceable water molecules which must be accurately located for optimal docking-based drug discovery. However, although there is a plethora of methods to place water molecules in and around protein structures, there is, to the best of our knowledge, no such fully automated method for nucleic acids, which are significantly more polar and solvated than proteins. We report herein a new method, SPLASH'EM (Solvation Potential Laid around Statistical Hydration on Entire Macromolecules) developed to place water molecules within the binding cavity of nucleic acids. This fast method was shown to have high agreement with water positions in crystal structures and will therefore provide essential information to medicinal chemists.

Torsional Energy Barriers of Biaryls Could Be Predicted by Electron Richness/Deficiency of Aromatic Rings; Advancement of Molecular Mechanics toward Atom-Type Independence

“…Consequently, there are still many ongoing developments in FFs. [46][47][48][49][50] Finally, in the future, H-TEQ 4.0 should be further extended to be applicable to all dihedral angles. Supporting Information.…”

How ‘Protein-Docking’ Translates into the New Emerging Field of Docking Small Molecules to Nucleic Acids?

“…It is built on the most frequent interactions observed in crystal complexes [62]. Recently, methods like the 3D-RISM methods [60] or the SPLASH'EM scoring function [63] allowing waters and cations site-prediction during structure optimization aimed at addressing this challenging task. The accuracy of these methods still suffers from the limited number of nucleic acid-ligand solved 3D structures [63].…”

Structured Waters Mediate Small Molecule Binding to G-Quadruplex Nucleic Acids

“…Several high-resolution crystallographic studies of native GQs [112][113][114][115] and GQligand complexes [71,74,75,80,81,98,100,116,117] have reported that water molecules are intimately associated with GQ sites and with bound ligand. It is well-established for DNA-, RNA- [118], and protein-ligand complexes [119][120][121][122][123] that water molecules can play critical target-ligand mediation roles. The present work analyzes water arrangements in several GQ-ligand complexes (PDB id 3CE5, 3NZ7, and 3UYH) [74,81,100] that are of sufficient resolution to give confidence in the significance of the arrangements, to better understand the role and the consequences of discrete water molecules associated with ligand binding.…”

“…This has been recognized in several studies for example, refs. [118,131]. Prediction of water positions and mobilities in ligand complexes can be made using molecular dynamics [131], although this has only rarely been been used to date for GQ systems [132].…”

“…Prediction of water positions and mobilities in ligand complexes can be made using molecular dynamics [131], although this has only rarely been been used to date for GQ systems [132]. The prediction of water positions having low mobility in nucleic acids by use of a specially generated water force field together with statistical scoring has led to the development of an automated method, termed "SPLASH'EM" (Solvation Potential Laid around Statistical Hydration on Entire Macromolecules) [118], which has given results for duplex DNA and some RNA structures in good agreement with experiment. It will be interesting to see this type of approach used for those GQ ligand complexes for which there is high resolution structural data, as well as therapeutically important GQ drug targets such as that from the KRAS promoter sequence [114].…”