The Role of Water in the Stability of Wild-type and Mutant Insulin Dimers

Raghunathan, Shampa and El Hage, Krystel and Desmond, Jasmine L. and Zhang, Lixian and Meuwly, Markus. (2018) The Role of Water in the Stability of Wild-type and Mutant Insulin Dimers. Journal of Physical Chemistry B, 122 (28). pp. 7038-7048.

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Official URL: https://edoc.unibas.ch/94215/

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Insulin dimerization and aggregation play important roles in the endogenous delivery of the hormone. One of the important residues at the insulin dimer interface is Phe B24 , which is an invariant aromatic anchor that packs toward its own monomer inside a hydrophobic cavity formed by Val B12 , Leu B15 , Tyr B16 , Cys B19 , and Tyr B26 . Using molecular dynamics and free-energy simulations within explicit solvent, the structural and dynamical consequences of mutations of Phe at position B24 to glycine (Gly), alanine (Ala), and d -Ala and the des-PheB25 variant are quantified. Consistent with experiments, it is found that the Gly and Ala modifications lead to insulin dimers with reduced stability by 4 and 5 kcal/mol from thermodynamic integration and 4 and 8 kcal/mol from results using molecular mechanics-generalized Born surface area, respectively. Given the experimental difficulties to quantify the thermodynamic stability of modified insulin dimers, such computations provide a valuable complement. Interestingly, the Gly mutant exists as a strongly and a weakly interacting dimer. Analysis of the molecular dynamics simulations shows that this can be explained by water molecules that replace direct monomer-monomer H-bonding contacts at the dimerization interface involving residues B24 to B26. It is concluded that such solvent molecules play an essential role and must be included in future insulin dimerization studies.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Physikalische Chemie (Meuwly)
UniBasel Contributors:Meuwly, Markus
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Chemical Society
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Apr 2023 09:51
Deposited On:03 Apr 2023 09:13

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