Complexity in Modeling and Understanding Protonation States: Computational Titration of HIV‐1‐Protease–Inhibitor Complexes

Abstract

The computational-titration (CT) algorithm based on the 'natural' Hydropathic INTeractions (HINT) force field is described. The HINT software model is an empirical, non-Newtonian force field derived from experimentally measured partition coefficients for solvent transfer between octanol and H(2)O (log P(o/w)). The CT algorithm allows the identification, modeling, and optimization of multiple protonation states of residues and ligand functional groups at the protein-ligand active site. The importance of taking into account pH and ionization states of residues, which strongly affect the process of ligand binding, for correctly predicting binding free energies is discussed. The application of the CT protocol to a set of six cyclic inhibitors in their complexes with HIV-1 protease is presented, and the advance of HINT as a virtual-screening tool is outlined.

Web application for studying the free energy of binding and protonation states of protein–ligand complexes based on HINT

“…The newly available computational titration web service is based on the computational titration algorithm62 implemented in the HINT program. While a flow chart of this algorithm has previously been published,60 Figure 1 contextualizes it within the web server.…”

“…In a second study, computational titration experiments for HIV-1 protease with six small molecule inhibitors of this enzyme were performed to optimize protonation state models. Binding energies for five ligands out of six were within an average error of 2.5 kcal mol −1 62. Modeling these interactions with other methods would have been very challenging, because these systems can assume many thousands of different ionizations state combinations 69.…”

“…The speed of HINT thus allows optimization of these ill-defined molecular features in a reasonable time frame. This process encompasses the computational titration algorithm for which some aspects have been described previously 60,61,62,63. In this report, we are describing an online version of the HINT-based computational titration method, i.e., a free web service for studying protonation states and Gibbs free energies of binding for protein-ligand complexes.…”

Molecular Docking: From Lock and Key to Combination Lock

“…In addition to managing issues associated with protein flexibility and solvent, both the computational intensities and uncertainties of the docking problem are compounded for protein∷ligand systems with variable ionization states, and contributions of metals and counter ions [26]. Protein ligand interactions are sensitive to subtle changes in microenvironment of the binding site.…”

“…New algorithms such as the computational titration protocol implemented in Hydropathic Interaction (HINT) seek to identify and optimize all possible protonation states so that rational models with atomic details can be constructed and applied to model ligand-binding energetic [26,30,31]. By modeling all ionizable residues in the binding pocket, and calculating all the possible protonation states of residues and functional groups within the active site, the computational-titration methodology realistically samples the dynamic behavior of labile H-atoms in the active site microenvironment.…”