Molecular dynamics simulations of the insulin family proteins & their receptors

Diabetes is one of the top causes of death, with the number of people diagnosed constantly increasing. Consequently, finding therapeutic candidates for insulin has become urgent. However, many critical questions are still unclear regarding insulin activation, and the activation process of the other insulin-family proteins, namely insulin-like growth factor I (IGF-I) and II (IGF-II). Deficiency of these proteins can lead to chronic diseases, with insulin being involved in diabetes and IGFs in cancer. To this end, this thesis presents the first molecular dynamics (MD) simulations of insulin to reveal new insights into its activation, which involves the B chain C-terminal (BC-CT) and its hydrophobic core. MD simulations of the IGFs are also presented for the first time, enabling comparison of their activation mechanisms. Additionally, this thesis presents a comprehensive computational study with the aim to predict the effect of mutations on insulin. The key results presented in this thesis are as follows: 1) Insulin activation is associated with the opening of the BC-CT and is stochastic in nature; 2) Insulin comprises three conformations, namely closed (inactive), open (active) and wide-open (active that fits the IR interface), with the closed conformation being the dominant one and the wide-open occurring rarely; 3) The F24 residue plays a hinge role, and Y26 is the critical residue during the activation; 4) IGFs activation is similar to insulin, however their activation involves two opening locations; 5) The two openings in IGF-I occur simultaneously, while in IGF-II independently indicating different activation mechanisms; 6) IGF-II appears to be hyperactive compared to IGF-I; 7) The hinge interaction and the hydrophobic interactions play a crucial role in the stability and activity of IGFs and insulin; 8) The analysis used to study the effect of mutations of insulin can be readily applied to any set of mutations to guide future drug development for insulin