DRoP: Automated detection of conserved solvent‐binding sites on proteins

Abstract

Water and ligand binding play critical roles in the structure and function of proteins, yet their binding sites and significance are difficult to predict a priori. Multiple solvent crystal structures (MSCS) is a method where several X‐ray crystal structures are solved, each in a unique solvent environment, with organic molecules that serve as probes of the protein surface for sites evolved to bind ligands, while the first hydration shell is essentially maintained. When superimposed, these structures contain a vast amount of information regarding hot spots of protein‐protein or protein‐ligand interactions, as well as conserved water‐binding sites retained with the change in solvent properties. Optimized mining of this information requires reliable structural data and a consistent, objective analysis tool. Detection of related solvent positions (DRoP) was developed to automatically organize and rank the water or small organic molecule binding sites within a given set of structures. It is a flexible tool that can also be used in conserved water analysis given multiple structures of any protein independent of the MSCS method. The DRoP output is an HTML format list of the solvent sites ordered by conservation rank in its population within the set of structures, along with renumbered and recolored PDB files for visualization and facile analysis. Here, we present a previously unpublished set of MSCS structures of bovine pancreatic ribonuclease A (RNase A) and use it together with published structures to illustrate the capabilities of DRoP.

Fragment Binding to the Nsp3 Macrodomain of SARS-CoV-2 Identified Through Crystallographic Screening and Computational Docking

“…3 D). Extending fragments to displace the water molecules at other frequently populated sites could help to quantify the contribution of water networks to Mac1, and to provide a test set for computational methods that seek to exploit solvent dynamics for ligand optimization ( 61 – 63 ).…”

Water in Ras Superfamily Evolution

“…The location of conserved water across many related crystal structures is a daunting task due to the large number of water‐binding sites in high‐resolution structures and the fact that random water numbering is used for each independently solved structure. We have automated the search for conserved water positions by developing the DRoP tool (Detection of Related Solvent Positions) . DRoP takes multiple PDB files through a public server (http://dropinthemattoslab.org), superimposes the coordinates, transfers symmetry‐related water molecules to the site closest to the protein and ranks the water positions according to the frequency in which they are occupied and clustered across the structures in the set.…”

Quantum Chemical Microsolvation by Automated Water Placement

“…However, in biomolecular simulations, the quantification of solute–solvent interactions and the identification of hydration sites—that is, the location of water molecules that show slow or no movement during the simulation—are an important goal due to its relevance in drug design [ 35 , 36 , 37 , 38 , 39 , 40 ]. Several computational tools exist to aid this procedure [ 37 , 39 , 40 , 41 ]. For example, grid inhomogeneous solvation theory (GIST) allows the analysis and thermodynamic quantification of the solute–solvent interaction on a grid over the whole trajectory [ 42 , 43 ].…”