Biology subjects

Chatterji, M.

Publications and source records attributed to Chatterji, M..

2 recordsLinked to original sources

bioRxiv2023

Mapping Structural Drivers of Insulin and its Analogs at the IGF-1 Receptor Using Molecular Dynamics and Free Energy Calculations

Insulin and insulin-like growth factor-1 receptors (IR, IGF-1R) belong to the family of receptor tyrosine kinases (RTKs), and share close structural resemblance. However, these receptors exhibit distinct activity profiles and functions in vivo. Binding of insulin to IGF-1R results in additional growth-factor-like behavior and cell proliferation, but its [~]100-fold reduced affinity to IGF-1R limits off-target activity. However, insulin analogs with increased potency at IGF-1R have oncogenicity as a key safety concern. Hence, the ability to accurately predict potency of novel analogs at IGF-1R could represent a key breakthrough towards rational insulin design. To date, a comprehensive molecular level understanding of insulin interactions at IGF-1R has remained elusive. This study capitalized on recent advancements in structural biology that provided high resolution structures of IGF-1R bound to IGF-1 and insulin. Initially, molecular dynamics (MD) simulations were employed to unravel the intricate interactions that characterize the receptor-ligand pairs. Next, free energy perturbation (FEP) calculations were performed to understand the increased affinity observed in insulin analogs, X10 and glargine. Subsequently, multiple mutations at the B10 position of insulin spanning different activities at IGF-1R and different metabolites of insulin glargine, encompassing various mitogenic potencies were studied using FEP. The calculations successfully captured directional shifts in potency for all studied mutants, with approximately 50% of the predicted values falling within 1 kcal/mol of experiment. Beyond its impressive accuracy, FEPs ability to provide a detailed understanding of protein- and solvent-mediated contributions to the observed functional profiles underscores its utility in designing safe IGF-1R selective novel insulin analogs.

biophysics↗

bioRxiv2022

Mapping the Structural Drivers of Insulin Recognition and Specificity Using Molecular Dynamics and Free Energy Calculations

A century on from the discovery of insulin, a complete understanding of insulin interactions with the insulin receptor (IR) at atomic level remains elusive. In this work, we have leveraged recent advancements in structural biology that have resulted in multiple high-resolution structures of the insulin-IR complex. As a first step, we employed molecular dynamics (MD) simulations to unravel atomic insights into the interactions between insulin-IR complexes in order to better understand ligand recognition at the receptor. The MD simulations were followed up with free energy perturbation (FEP) calculations to discriminate between and elucidate the drivers for ligand association for various natural and man-made insulin analogs. As an example, these calculations were utilized to understand the molecular mechanisms that characterized the loss-of-function seen in disease-associated insulin mutations seen in different populations. Further, multiple man-made insulin analogs spanning a range of potencies, mutations, and sequence lengths were studied using FEP and a comprehensive molecular level map of potency determinants were established. [~]85% of FEP calculations captured the direction of shift of potency, and in [~]53% of cases the predictions were within 1 kcal/mol of experiment. The impressive accuracy of FEP in recapitulating functional profiles across such a span of insulin analogs and potency profiles provided clear evidence of its utility in computational mutagenesis. In addition to the impressive accuracy, the ability of FEP to provide a dissected understanding of protein residue, solvent and solvent-mediated contributions to binding energy clearly establishes its utility in the design of novel insulins and peptides in general.

biophysics↗