The fundamental role of flexibility on the strength of molecular binding

Abstract

Non-covalent molecular association underlies a diverse set of biologically and technologically relevant phenomena, including the action of drugs on their biomolecular targets and self- and supra-molecular assembly processes. Computer models employed to model binding frequently use interaction potentials with atomistic detail while neglecting the thermal molecular motions of the binding species. However, errors introduced by this simplification and, more broadly, the thermodynamic consequences of molecular flexibility on binding, are little understood. Here, we isolate the fundamental relationship of molecular flexibility to binding thermodynamics via simulations of simplified molecules with a wide range of flexibilities but the same interaction potential. Disregarding molecular motion is found to generate large errors in binding entropy, enthalpy and free energy, even for molecules that are nearly rigid. Indeed, small decreases in rigidity markedly reduce affinity for highly rigid molecules. Remarkably, precisely the opposite occurs for more flexible molecules, for which increasing flexibility leads to stronger binding affinity. We also find that differences in flexibility suffice to generate binding specificity: for example, a planar surface selectively binds rigid over flexible molecules. Intriguingly, varying molecular flexibility while keeping interaction potentials constant leads to near-linear enthalpy-entropy compensation over a wide range of flexibilities, with the unexpected twist that increasing flexibility produces opposite changes in entropy and enthalpy for molecules in the flexible versus the rigid regime. Molecular flexibility is thus a crucial determinant of binding affinity and specificity and variations in flexibility can lead to strong yet non-intuitive consequences.

Thermodynamic studies of a series of homologous HIV-1 TAR RNA ligands reveal that loose binders are stronger Tat competitors than tight ones

“…Our results are in line with a recently reported computer modeling study that predicts that varying molecular flexibility while keeping the same interaction network leads to near-linear EEC (39). Moreover, when the receptor is flexible, increasing ligand flexibility leads to stronger binding affinity.…”

Mechanical Carbohydrate Sensors Based on Soft Hydrogel Particles

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In silico analysis of the tryptophan hydroxylase 2 (TPH2) protein variants related to psychiatric disorders

“…Protein flexibility is determinant for binding affinity and specificity. Thus, flexibility alterations can lead to strong and nonintuitive consequences for protein binding properties [34]. The flexibility alterations observed during the MD simulations of the P206S, R303W, and R441H variants indicate that these mutations may affect TPH2 binding affinity and specificity, particularly at the oligomerization and catalytic domains.…”