HINT, a code for understanding the interaction between biomolecules: a tribute to Donald J. Abraham

Abstract

A long-lasting goal of computational biochemists, medicinal chemists, and structural biologists has been the development of tools capable of deciphering the molecule–molecule interaction code that produces a rich variety of complex biomolecular assemblies comprised of the many different simple and biological molecules of life: water, small metabolites, cofactors, substrates, proteins, DNAs, and RNAs. Software applications that can mimic the interactions amongst all of these species, taking account of the laws of thermodynamics, would help gain information for understanding qualitatively and quantitatively key determinants contributing to the energetics of the bimolecular recognition process. This, in turn, would allow the design of novel compounds that might bind at the intermolecular interface by either preventing or reinforcing the recognition. HINT, hydropathic interaction, was a model and software code developed from a deceptively simple idea of Donald Abraham with the close collaboration with Glen Kellogg at Virginia Commonwealth University. HINT is based on a function that scores atom–atom interaction using LogP, the partition coefficient of any molecule between two phases; here, the solvents are water that mimics the cytoplasm milieu and octanol that mimics the protein internal hydropathic environment. This review summarizes the results of the extensive and successful collaboration between Abraham and Kellogg at VCU and the group at the University of Parma for testing HINT in a variety of different biomolecular interactions, from proteins with ligands to proteins with DNA.

Three-Dimensional Interaction Homology: Deconstructing Residue–Residue and Residue–Lipid Interactions in Membrane Proteins

“…Interatomic interactions were scored with the HINT forcefield [ 32 , 33 ]. The fundamental parameter, the hydrophobic atom constant, is an atom-level logP o/w that uses the defined fragments and factors of the Hansch and Leo methodology [ 77 , 78 ].…”

“…These maps encode the position, intensity, and type of atom–atom interactions between the residue and other residues in contact or near-contact to it. Mathematical expressions have been set out in previous works [ 30 , 33 , 35 ]. Map data were calculated for sidechain atoms of all residues in this study with individual maps for the four interaction classes: favorable polar, unfavorable polar, favorable hydrophobic, and unfavorable hydrophobic.…”

“…While self-evident, our hypothesis de-emphasizes sequence homology in favor of a residue-level hydropathic valence , which is the set of interactions each residue ideally would make: involving interaction type (both favorable—like hydrophobic and hydrogen bonds—and unfavorable—like repulsive Coulombic and desolvation), interaction strength, and their 3D spatial arrangement. We encoded these interaction sets in 3D contourable hydropathic interaction maps calculated using a feature of the HINT (Hydropathic INTeractions) modeling system [ 32 , 33 ]. Crucially, after clustering, there are a limited number of unique maps and they are dependent on the residue type and backbone angles.…”