Molecular Lipophilicity in Protein Modeling and Drug Design

Abstract

Hydrophobic interactions play a key role in the folding and maintenance of the 3-dimensional structure of proteins, as well as in the binding of ligands (e.g. drugs) to protein targets. Therefore, quantitative assessment of spatial hydrophobic (lipophilic) properties of these molecules is indispensable for the development of efficient computational methods in drug design. One possible solution to the problem lies in application of a concept of the 3-dimensional molecular hydrophobicity potential (MHP). The formalism of MHP utilizes a set of atomic physicochemical parameters evaluated from octanol-water partition coefficients (log P) of numerous chemical compounds. It permits detailed assessment of the hydrophobic and/or hydrophilic properties of various parts of molecules and may be useful in analysis of protein-protein and protein-ligand interactions. This review surveys recent applications of MHP-based techniques to a number of biologically relevant tasks. Among them are: (i) Detailed assessment of hydrophobic/hydrophilic organization of proteins; (ii) Application of this data to the modeling of structure, dynamics, and function of globular and membrane proteins, membrane-active peptides, etc. (iii) Employment of the MHP-based criteria in docking simulations for ligands binding to receptors. It is demonstrated that the application of the MHP-based techniques in combination with other molecular modeling tools (e.g. Monte Carlo and molecular dynamics simulations, docking, etc.) permits significant improvement to the standard computational approaches, provides additional important insights into the intimate molecular mechanisms driving protein assembling in water and in biological membranes, and helps in the computer-aided drug discovery process.

Modular Organization of α-Toxins from Scorpion Venom Mirrors Domain Structure of Their Targets, Sodium Channels

“…For example, calculation of hydrophobic "complementarity" in the binding pockets at the protein/ligand interface uncovers important principles in molecular recognition, and this idea may be applied to improve docking results (15,28). Moreover, surface hydrophobicity is a good measure for conformational transitions (42,43) and generally "tags" areas of intermolecular recognition (16).…”

“…Molecular Hydrophobicity Potential (MHP) CalculationsThe MHP approach assumes that each atom in a molecule possesses its "intrinsic" value of hydrophobicity (atomic hydrophobicity constant), taking the molecular topology into account (16,17). These constants have been determined from the database of experimental log P values for a large number of organic compounds (27); MHP at any given point is calculated as a superposition of contributions created by each atom, monotonically decay-ing with distance.…”

“…Mammal ␣-Toxins Possess Prominently Hydrophilic Specificity Modules-To compare the average dynamic hydrophobicity in the three groups of toxins, we employed the MHP approach (16). It represents a powerful tool to calculate spatial distribution of hydrophobic/hydrophilic properties proven to be important in molecular recognition (15).…”

“…A number of techniques have been developed for delineation of specific regions on molecular surfaces, which can be potentially involved in protein-protein recognition. Detailed mapping of surface hydrophobic/hydrophilic properties of two interacting molecules has been widely used for protein-ligand and proteinprotein interactions (15)(16)(17)(18), where molecular surface properties are projected onto a plane, cylinder, or sphere, aiding reduction of complexity and facilitating relatively straightforward comparison of projected "maps" rather than matching complex three-dimensional shapes.…”

Conformational Dynamics Associated with Ligand Binding to Vertebrate Hexa-coordinate Hemoglobins

“…Reeder et al (2011) proposed that the extended N-and C-terminal may be responsible for the protein-lipid interactions, but this hypothesis has not been experimentally tested. Protein-ligand and protein-protein interactions are often facilitated by formation of hydrophobic patches or clefts on the protein's surface, leading to association of the ligand or protein through hydrophobic interactions with the target protein (Efremov et al, 2007).…”