SEARCHING CONFORMATIONS FOR THE AMYLIN PEPTIDE: REPLICA EXCHANGE SIMULATIONS AND COMPARISON WITH THE EXPERIMENT

Amylin (hIAPP) is a peptide sequence comprising 37 aminoacids that is synthesized in the pancreas. Type 2 diabetes is a disease in which the hormone peptide aggregates adopting a well-defined beta-cross structure, while in solution the molecule is intrinsically disordered, being considered an Intrinsic Disordered Protein (IDP). Among available tools to investigate the conformation of the peptide in solution, both experimental and theoretical approaches can extract valuable information. In particular, theoretical methods such as Molecular Dynamics (MD) simulations can offer insight on the peptide’s secondary structure, which can be compared to experimental Circular Dichroism (CD) data. With a shallow potential energy surface, a number of distinct local minima may be relevant to compare with experimental CD data, which can be challenging to sample in equilibrium atomistic MD. Strategies to circumvent this problem while maintaining the atomistic resolution include enhanced sampling simulations or replica exchange simulations. In this work, we propose to explore the conformations of the peptide employing implicit solvent with the AMBER forcefield ff14SBonlysc with Generalized Born as a low computational cost method. While the solvent structure plays a major role on the structure of any biomolecule, the advantage of using replica exchange is that it does not require a reaction coordinate a priori. In the absence of water, one can employ 8 to 16 replicas, depending on the temperature range. Conformations are clustered according to structural properties such as the RMSD and Radius of Gyration and the secondary structure is accounted with the DSSP algorithm, which can be directly correlated with deconvoluted experimental CD data. Results suggest that the peptide can adopt folded conformations such as α-helix and β-sheet and also partially folded and disordered conformations, emphasizing the complexity of the peptide in solution.