Protein Hydration Waters Are Susceptible to Unfavorable Perturbations

Rego, Nicholas B.; Xi, Erte; Patel, Amish J.

doi:10.1021/jacs.8b11448

Cited by 43 publications

(55 citation statements)

References 73 publications

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“…34 Furthermore, it was shown how proteins can use hydrophobicity to shape biomolecular interactions by driving solvated binding sites away or towards the wet state depending on their chemistry and topology, 35 thereby rendering the hydration shells susceptible to perturbations. 36 In this work, we use all-atom molecular dynamics (MD) simulations to characterize the atomic-level details of the coupling of ligand motion to solvent fluctuations in a protein-ligand system. Ubiquitin (UBQ) was used as a model protein to investigate the impact of protein flexibility on the dynamics of ligand binding to a hydrophobic protein surface patch.…”

Section: Introductionmentioning

confidence: 99%

Protein flexibility reduces solvent-mediated friction barriers of ligand binding to a hydrophobic surface patch

Päslack

Schäfer

Heyden

2021

Phys. Chem. Chem. Phys.

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Section: Introductionmentioning

confidence: 99%

Protein flexibility reduces solvent-mediated friction barriers of ligand binding to a hydrophobic surface patch

Päslack

Schäfer

Heyden

2021

Phys. Chem. Chem. Phys.

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“…Analysis of cases where these are not well captured (e.g., F1174S, I1170N) will provide valuable insight into how to extend our consideration beyond hydrogen bond occupancy in the αC-helix and the activation loop. For the latter, the inability of SASA analysis of R-spine residues to distinguish activating from nonactivating mutations suggests that more sophisticated scoring functions for hydrophobic analysis based on free energies will need to be invoked (11,70). Reanalysis of the mutations "missed" by our analysis here will help guide the inclusion of additional dimensions in scoring functions to improve BACC and also shed additional light on activation mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Computational studies of anaplastic lymphoma kinase mutations reveal common mechanisms of oncogenic activation

Patil

Jordan

Park

et al. 2021

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

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Kinases play important roles in diverse cellular processes, including signaling, differentiation, proliferation, and metabolism. They are frequently mutated in cancer and are the targets of a large number of specific inhibitors. Surveys of cancer genome atlases reveal that kinase domains, which consist of 300 amino acids, can harbor numerous (150 to 200) single-point mutations across different patients in the same disease. This preponderance of mutations—some activating, some silent—in a known target protein make clinical decisions for enrolling patients in drug trials challenging since the relevance of the target and its drug sensitivity often depend on the mutational status in a given patient. We show through computational studies using molecular dynamics (MD) as well as enhanced sampling simulations that the experimentally determined activation status of a mutated kinase can be predicted effectively by identifying a hydrogen bonding fingerprint in the activation loop and the αC-helix regions, despite the fact that mutations in cancer patients occur throughout the kinase domain. In our study, we find that the predictive power of MD is superior to a purely data-driven machine learning model involving biochemical features that we implemented, even though MD utilized far fewer features (in fact, just one) in an unsupervised setting. Moreover, the MD results provide key insights into convergent mechanisms of activation, primarily involving differential stabilization of a hydrogen bond network that engages residues of the activation loop and αC-helix in the active-like conformation (in >70% of the mutations studied, regardless of the location of the mutation).

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“…These results strongly support the growing consensus that hydrophobic interactions are context dependent, where the proximity of nonpolar and polar units to each other impacts the surface hydrophobicity/hydrophilicity. Indeed, similar ideas have been utilized to direct mutations on therapeutic proteins to minimize aggregation (8), to characterize protein-ligand interactions (9,10), and to moderate longrange interactions between hydrophobic surfaces in water (11).…”

Section: What About Heterogeneous Surfaces?mentioning

confidence: 99%