Entropy—enthalpy compensation: Fact or artifact?

Sharp, Kim A.

doi:10.1110/ps.37801

Cited by 394 publications

(435 citation statements)

References 15 publications

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“…In this way, the EET mechanism can lead to highly linear entropy-enthalpy compensation. This observation is broadly consistent with prior suggestions, derived from plausible mathematical models rather than detailed simulation, regarding the importance of delicately poised equilibria (46), large fluctuations, and a high density of states (47)(48)(49)(50)(51). Although the EET mechanism can, in this manner, generate a highly linear correlation between entropy and enthalpy, it can also generate other thermodynamic patterns.…”

Section: Discussionsupporting

confidence: 90%

Entropy–enthalpy transduction caused by conformational shifts can obscure the forces driving protein–ligand binding

Fenley

Muddana

Gilson

2012

Proc. Natl. Acad. Sci. U.S.A.

116

150

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Molecular dynamics simulations of unprecedented duration now can provide new insights into biomolecular mechanisms. Analysis of a 1-ms molecular dynamics simulation of the small protein bovine pancreatic trypsin inhibitor reveals that its main conformations have different thermodynamic profiles and that perturbation of a single geometric variable, such as a torsion angle or interresidue distance, can select for occupancy of one or another conformational state. These results establish the basis for a mechanism that we term entropy-enthalpy transduction (EET), in which the thermodynamic character of a local perturbation, such as enthalpic binding of a small molecule, is camouflaged by the thermodynamics of a global conformational change induced by the perturbation, such as a switch into a high-entropy conformational state. It is noted that EET could occur in many systems, making measured entropies and enthalpies of folding and binding unreliable indicators of actual thermodynamic driving forces. The same mechanism might also account for the high experimental variance of measured enthalpies and entropies relative to free energies in some calorimetric studies. Finally, EET may be the physical mechanism underlying many cases of entropy-enthalpy compensation.T he entropic and enthalpic components of free energy can be informative regarding the mechanisms of biophysical processes, like protein folding and protein-ligand binding. Moreover, information on changes in entropy and enthalpy can usefully guide the design of improved drug molecules (1), with advantageous specificity (2) and physical properties (3). However, calorimetric studies of biomolecular binding and folding often reveal unexpected changes in entropy and enthalpy that are difficult to interpret in terms of physical driving forces (4-8). Some of these puzzling results are instances of entropy-enthalpy compensation (9), a common but not universal (10, 11) phenomenon in which perturbations of a system that increase the enthalpy also increase the entropy or vice versa; therefore, the net change in the free energy remains small. Experimental error in measured enthalpies, particularly when obtained by the relatively imprecise van 't Hoff method, can generate spurious entropy-enthalpy compensation (12); the nonphysical operation of Berkson's paradox (selection bias) (13) can also generate this compensation. However, analysis of collected calorimetric data for protein-ligand binding indicates that entropy-enthalpy compensation is a genuine and common physical phenomenon (13).Today, novel computational technologies, such as graphical processor units (14-17) and the specialized Anton computer (18), are enabling dramatically longer molecular dynamics (MD) simulations than hitherto feasible. The enormous conformational sampling power of these technologies has the potential to open a new window on the molecular mechanisms underlying the thermodynamics of biomolecular systems. For example, it can provide increasingly accurate estimates of thermodynamic quantities that ...

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Section: Discussionsupporting

confidence: 90%

Entropy–enthalpy transduction caused by conformational shifts can obscure the forces driving protein–ligand binding

Fenley

Muddana

Gilson

2012

Proc. Natl. Acad. Sci. U.S.A.

116

150

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“…These locations correspond to the low orientational entropy locations seen above, indicating water molecules that are low in both energy and entropy, as might be expected, given the common, though debated, phenomenon of entropy-enthalpy compensation. [66][67][68][69][70][71] Second, there is a shell around the entire host comprising water molecules that have unfavorable energies because of their interactions with the host's repulsive Lennard-Jones wall. However, this shell is lightly populated, so water molecules in this region do not significantly contribute to the overall energy of solvation.…”

Section: Regular Host a Translational Entropy And Water Densitymentioning

confidence: 99%

Grid inhomogeneous solvation theory: Hydration structure and thermodynamics of the miniature receptor cucurbit[7]uril

Nguyen

Young²,

Gilson³

2012

The Journal of Chemical Physics

302

506

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The displacement of perturbed water upon binding is believed to play a critical role in the thermodynamics of biomolecular recognition, but it is nontrivial to unambiguously define and answer questions about this process. We address this issue by introducing grid inhomogeneous solvation theory (GIST), which discretizes the equations of inhomogeneous solvation theory (IST) onto a threedimensional grid situated in the region of interest around a solute molecule or complex. Snapshots from explicit solvent simulations are used to estimate localized solvation entropies, energies, and free energies associated with the grid boxes, or voxels, and properly summing these thermodynamic quantities over voxels yields information about hydration thermodynamics. GIST thus provides a smoothly varying representation of water properties as a function of position, rather than focusing on hydration sites where solvent is present at high density. It therefore accounts for full or partial displacement of water from sites that are highly occupied by water, as well as for partly occupied and water-depleted regions around the solute. GIST can also provide a well-defined estimate of the solvation free energy and therefore enables a rigorous end-states analysis of binding. For example, one may not only use a first GIST calculation to project the thermodynamic consequences of displacing water from the surface of a receptor by a ligand, but also account, in a second GIST calculation, for the thermodynamics of subsequent solvent reorganization around the bound complex. In the present study, a first GIST analysis of the molecular host cucurbit [7]uril is found to yield a rich picture of hydration structure and thermodynamics in and around this miniature receptor. One of the most striking results is the observation of a toroidal region of high water density at the center of the host's nonpolar cavity. Despite its high density, the water in this toroidal region is disfavored energetically and entropically, and hence may contribute to the known ability of this small receptor to bind guest molecules with unusually high affinities. Interestingly, the toroidal region of high water density persists even when all partial charges of the receptor are set to zero. Thus, localized regions of high solvent density can be generated in a binding site without strong, attractive solute-solvent interactions.

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“…In other words, why didn't we observe a gain in electrostatic energy upon moving from the encounter complex toward the final complex and vice versa? A possible explanation would be that the penalty paid for the desolvation of charges is apparently similar to the gain in Coulombic energy upon bringing them together (29,30). The two-step pathway for association observed for the RalGDSRBD͞Ras interaction does not seem to be a unique case.…”

Section: Discussionmentioning

confidence: 99%

Electrostatically optimized Ras-binding Ral guanine dissociation stimulator mutants increase the rate of association by stabilizing the encounter complex

Kiel

Selzer

Shaul

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

104

128

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Association of two proteins can be described as a two-step process, with the formation of an encounter complex followed by desolvation and establishment of a tight complex. Here, by using the computer algorithm PARE, we designed a set of mutants of the Ras effector protein Ral guanine nucleotide dissociation stimulator (RalGDS) with optimized electrostatic steering. The fastest binding RalGDS mutant, M26K,D47K,E54K, binds Ras 14-fold faster and 25-fold tighter compared with WT. A linear correlation was found between the calculated and experimental data, with a correlation coefficient of 0.97 and a slope of 0.65 for the 24 mutants produced. The data suggest that increased electrostatic steering specifically stabilizes the encounter complex and transition state. This conclusion is backed up by ⌽ analysis of the encounter complex and transition state of the RalGDS M26K,D47K,E54K ͞Ras complex, with both values being close to 1. Upon further formation of the final complex, the increased Coulombic interactions are probably counterbalanced by the cost of desolvation of charges, keeping the dissociation rate constant almost unchanged. This mechanism is also reflected by the mutual compensation of enthalpy and entropy changes quantified by isothermal titration calorimetry. The binding constants of the faster binding RalGDS mutants toward Ras are similar to those of Raf, the most prominent Ras effector, suggesting that the design methodology may be used to switch between signal transduction pathways.

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Entropy—enthalpy compensation: Fact or artifact?

Cited by 394 publications

References 15 publications

Entropy–enthalpy transduction caused by conformational shifts can obscure the forces driving protein–ligand binding

Entropy–enthalpy transduction caused by conformational shifts can obscure the forces driving protein–ligand binding

Grid inhomogeneous solvation theory: Hydration structure and thermodynamics of the miniature receptor cucurbit[7]uril

Electrostatically optimized Ras-binding Ral guanine dissociation stimulator mutants increase the rate of association by stabilizing the encounter complex

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