The reorganization energy of compounds upon binding to proteins, from dynamic and solvated bound and unbound states

Abstract

The intramolecular reorganization energy (ΔEReorg) of compounds upon binding to proteins is a component of the binding free energy, which has long received particular attention, for fundamental and practical reasons. Understanding ΔEReorg would benefit the science of molecular recognition and drug design. For instance, the tolerable strain energy of compounds upon binding has been elusive. Prior studies found some large ΔEReorg values (e.g. > 10 kcal/mol), received with skepticism since they imply excessive opposition to binding. Indeed, estimating ΔEReorg is technically difficult. Typically, ΔEReorg has been approached by taking two energy-minimized conformers representing the bound and unbound states, and subtracting their conformational energy. This is a drastic oversimplification, liable to conformational collapse of the unbound conformer. Instead, the present work applies extensive molecular dynamics (MD) and the modern OPLS3 force-field to simulate compounds bound and unbound states, in explicit solvent under physically relevant conditions. The thermalized unbound compounds populate multiple conformations, not reducible to one or a few energy-minimized conformers. The intramolecular energies in the bound and unbound states were averaged over pertinent conformational ensembles, and the reorganization enthalpy upon binding (ΔHReorg) deduced by subtraction. This was applied to 76 systems, including 43 approved drugs, carefully selected for i) the quality of the bioactive X-ray structures and ii) the diversity of the chemotypes, their properties and protein targets. It yielded comparatively low ΔHReorg values (median = 1.4 kcal/mol, mean = 3.0 kcal/mol). A new finding is the observation of negative ΔHReorg values. Indeed, reorganization energies do not have to oppose binding, e.g. when intramolecular interactions stabilize preferentially the bound state. Conversely, even with competing water molecules, intramolecular interactions can occur predominantly in the unbound compound, and be replaced by intermolecular counterparts upon protein binding. Such disruption of intramolecular interactions upon binding gives rise to occasional larger ΔHReorg values. Such counterintuitive larger ΔHReorg values may be rationalized as a redistribution of interactions upon binding, qualitatively compatible with binding.