An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder

Abstract

The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. However, structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, it entails an entropic penalty that counters complex formation. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Since hydrogen bonds have been described as essential for structural stability, here we investigate 469 such interactions across two diverse structure sets, comprising of 79 druglike and 27 fragment ligands, respectively. Completely constricted protein-ligand complexes are rare and may fulfill a functional role. Most complexes balance order and disorder by combining a single anchoring point with looser regions. 25% do not contain any robust hydrogen bond and may form loose structures. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design.

Exploring conformational preferences of proteins: ionic liquid effects on the energy landscape of avidin

“…2 The populations of the conformations follow statistical thermodynamic distributions, and the heights of the energy barriers separating the conformations dene the timescale of conformational transitions. [3][4][5] We can visualise that for a ligand-binding protein in solution, if the free energy barriers are low relative to the Boltzmann energy (k B T), thermal uctuations can lead to signicant populations of multiple conformers. 2,6 A ligand can then interact with the lowest energy conformer, or with one of a number of higher energy conformers that are populated in solution.…”

Probing the Highly Disparate Dual Inhibitory Mechanisms of Novel Quinazoline Derivatives against Mycobacterium tuberculosis Protein Kinases A and B

“…Estimated HBs were 149, 143, 132 and 126 respectively for 33 -PknB, 33 -PknA, 57 -PknA, 57 -PknB complexes. Higher HB counts associated with the 33 -bound complexes could deduce an increase in the stability of the proteins [ 43 , 44 ]. Relatively, reduced average HBs (PknA = 122, PknB = 123) in the unbound proteins could possibly indicate an increase in structural flexibility or instability [ 43 , 45 ].…”

Enthalpy–Entropy Compensation in Biomolecular Recognition: A Computational Perspective

“…Barril and co-workers investigated a large set of hydrogen-bonded protein–ligand complexes using SMD simulations to calculate the work necessary to break individual interactions. 12 These values are a measure of the robustness of the given interaction. Results reveal that a high content of robust hydrogen bonds is rare and that most complexes feature a single robust contact surrounded by a looser network of other interactions.…”