A λ-Dynamics Investigation of Insulin <i>Wakayama</i> and Other A3 Variant Binding Affinities to the Insulin Receptor.

ABSTRACT: Insulin Wakayama is a clinical insulin variant where a conserved valine at the third residue on insulin's A chain (Val^A3) is replaced with a leucine (Leu^A3), weakening insulin receptor (IR) binding by 140-500-fold. This severe impact on binding from a subtle modification has posed an intriguing problem for decades. Although experimental investigations of natural and unnatural A3 mutations have highlighted the sensitivity of insulin-IR binding at this site, atomistic explanations of these binding trends have remained elusive. We investigate this problem computationally using λ-dynamics free energy calculations to model structural changes in response to perturbations of the Val^A3 side chain and to calculate associated relative changes in binding free e

SUBMITTER: Barron MP 

PROVIDER: S-EPMC11268370 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature