Artificial protein cavities as specific ligand-binding templates: characterization of an engineered heterocyclic cation-binding site that preserves the evolved specificity of the parent protein 1 1Edited by R. Huber

Perspective: Alchemical free energy calculations for drug discovery

“…109,[140][141][142] These are relatively simple binding sites which bind small, fragment-like ligands and yet are susceptible the binding mode sampling problems discussed here. Much of the work in these sites has been with absolute free energy calculations (with notable exceptions 105,109,128 ), but the available high quality data pave the way for a careful examination of relative free energy calculations in this context.…”

(Thermo)dynamic Role of Receptor Flexibility, Entropy, and Motional Correlation in Protein–Ligand Binding

“…Ligand binding affects the flexibility of both the W191G cavity and 190-195 gating-loop regions, [10,14] which may induce full opening of the gating loop in the case of benzimidazole (bzi). [10] However, a number of X-ray structures [12] and molecular dynamics (MD) simulations [14] suggest that no major rearrangements occur in other regions of the W191G protein upon binding of small compounds.…”

“…[1][2][3][4][5][6][7][8] The binding of 2-amino-5-methylthiazole (2a5mt) to the W191G cavity mutant of cytochrome c peroxidase from E. coli (W191G) has been characterized by X-ray crystallography [9][10][11][12] and isothermal titration calorimetry [12] experiments, as well as by computational techniques. [13,14] This system is an ideal test case to investigate the magnitude of the entropy penalty to the binding free energy due to changes in receptor flexibility.…”

“…) have been measured [12] for thirteen ligands and are fully compatible with the receptor-entropy changes described in this work.…”

“…A change of (overall solute and solvent) molecular entropy [20,35] upon binding 2a5mt of about 30 kJ mol À1 was measured. [12] Therefore, the solute-solute component of the overall molecular entropy terms must be overcompensated by favorable solute-solvent and solvent-solvent effects. This latter hypothesis is also supported by the ordering effect on cavity water dynamics due to the K + ion in the W191G cavity, [14] which suggests a large and favorable solvent-solvent (reorganization) entropy change upon K + displacement and cavity desolvation.…”