Hydration Free Energies and Entropies for Water in Protein Interiors

Olano, L. Renee; Rick, Steven W.

doi:10.1021/ja049701c

Cited by 102 publications

(181 citation statements)

References 70 publications

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“…When focusing on the average value associated to each pocket, we obtain ⟨ΔG i ⟩ P1 = −1.6 ± 0.3 and ⟨ΔG i ⟩ P2 = −5.5 ± 0.4 kcal/mol for the domain and ⟨ΔG i ⟩ P1 = −1.5 ± 0.3 and ⟨ΔG i ⟩ P2 = −3.6 ± 0.5 kcal/mol for the domain. The values are close to previous estimates of the insertion free energy for water into the cavities of other proteins as the bacteriorhodopsin 48 , BPTI 50 , and kinase A 80 .…”

Section: Local Hydration Free Energiessupporting

confidence: 87%

“…The average ⟨ΔG i ⟩ is −1.8 and −1.6 kcal/ mol, for and . A comparable decrease of the favorable hydration was reported also for nonpolar cavities, and in a less extended temperature window for the favorable hydration of BPTI cavity 50 .…”

Section: Stability At High Temperaturesupporting

confidence: 82%

“…The value of the constant was chosen such that it reproduces the fluctuations of the oxygen around the reference site in the unbiased trajectory. This procedure avoids the definition of a static reference point in space and thus the need of fitting the protein structure to a reference configuration during the dynamics 50 .…”

Section: Free Energy Calculationsmentioning

confidence: 99%

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Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

et al. 2014

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In this work we address the question whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologues G-domains of different stability: the mesophilic G domain of the Elongation-Factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-α protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time-scale we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favourable for both systems, with the hyperthermophilic protein offering a slightly more favourable environment to host water molecules. We estimate that under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that at extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G-domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue.

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Section: Local Hydration Free Energiessupporting

confidence: 87%

Section: Stability At High Temperaturesupporting

confidence: 82%

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Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

et al. 2014

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“…One important approach involves using thermodynamic integration (TI) or related methods to compute the work of extracting an isolated water molecule from a binding pocket. [24][25][26][27][28] However, it may be difficult to apply this approach in settings of partly occupied water sites or sites where a removed water molecule would immediately be replaced by another from the bulk.…”

Section: Introductionmentioning

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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“…Frequently, buried water molecules can act as the H-bonding partners, but at enthalpic and entropic costs (18). Most of the buried hydroxyl or sulfhydryl protons showed strong NOEs (or exchange peaks) with water ( Table 2 and Fig.…”

Section: Resultsmentioning

confidence: 99%

Solution structure of p53 core domain: Structural basis for its instability

Pérez‐Cañadillas

Tidow

Freund

et al. 2006

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

161

221

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The 25-kDa core domain of the tumor suppressor p53 is inherently unstable and melts at just above body temperature, which makes it susceptible to oncogenic mutations that inactivate it by lowering its stability. We determined its structure in solution using stateof-the-art isotopic labeling techniques and NMR spectroscopy to complement its crystal structure. The structure was very similar to that in the crystal but far more mobile than expected. Importantly, we were able to analyze by NMR the structural environment of several buried polar groups, which indicated structural reasons for the instability. NMR spectroscopy, with its ability to detect protons, located buried hydroxyl and sulfhydryl groups that form suboptimal hydrogen-bond networks. We mutated one such buried pair, Tyr-236 and Thr-253 to Phe-236 and Ile-253 (as found in the paralogs p63 and p73), and stabilized p53 by 1.6 kcal͞mol. We also detected differences in the conformation of a mobile loop that might reflect the existence of physiologically relevant alternative conformations. The effects of temperature on the dynamics of aromatic residues indicated that the protein also experiences several dynamic processes that might be related to the presence of alternative hydrogen-bond patterns in the protein interior. p53 appears to have evolved to be dynamic and unstable.dynamics ͉ stability ͉ protein ͉ NMR ͉ isotope labeling

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Hydration Free Energies and Entropies for Water in Protein Interiors

Cited by 102 publications

References 70 publications

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

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

Solution structure of p53 core domain: Structural basis for its instability

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