A Molecular Dynamics Analysis of Insulin

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the Department of Chemistry and Physics, School of Molecular Sciences, College of Science, Health and Engineering, La Trobe University, Victoria, Australia.

Insulin is a vital protein hormone, whose discovery and structural understanding has been of critical importance, for the treatment of diabetes mellitus. However, the molecular mechanism, how it acts as an agonist on its cognate receptor, though heavily investigated, remains incompletely answered. There is now a strong body of evidence that indicates that when insulin binds to regions of its receptor, it unlocks a cascade of movements in the receptor and in the subsequent signal pathway. Here are provided some background, for understanding some of insulins structural biology and activity of specific residues, in relation to the structural overviews, here calculated for insulin models pertaining to different environments. Especially novel is a conjectured model of the IR binding up to 4 insulin’s and its physiological meaning. Furthermore, a complete intricate dynamical profile model of the solvated insulin monomer has been short of literature, which is here intricately provided by means of molecular dynamics (MD). In this thesis unprecedently long MD simulations of the insulin monomer have been sampled, providing a physiological model of its dynamics. A large part of this work pertained to the developing of analytical overview methods, for the specific analytical geometric queries, albeit adaptable to other protein models. This overview method was partly used to obtain analytical information and binding surfaces, from already reported insulin structures, i.e. in hexamers, bound to receptor fragments, and a NMR restrained solvent model. This innovatory depiction method is used as an example to get an analytical overview of oligomer aggregates and ligand receptor binding surfaces. The example being a complementing structural analytical overview for the classical hexamer structure of Baker et al. 1 and the insulin high affinity bound cross-link to its IR binding region by Weis et al. 2. Furthermore the NMR solvent model by Q. Hua et al. [3] were compared to its own restraints and an analytical overview provided. An analogous geometrical analysis was also applied to insulin in explicit solvent, from the highly dynamic and time dependent MD simulations, which were validated by means of comparing to the NMR restraints and extensive sampling. Moreover, the obtained structural analysis of this dynamic solvent MD model, is readily comparable to the other models depicted. The geometrical perspective obtained in this thesis, facilitates an understanding of solvated insulin dynamics and contiguous binding surfaces. The aim of the thesis being to aid in the development of novel insulin analogues or other molecules, for the treatment of diabetes.