A Computational Study of human Islet Amyloid Polypeptide Aggregation and its Inhibition

Abstract

quotThe aggregation of human islet amyloid polypeptide (hIAPP) stands at the nexus of Type II Diabetes (T2D) newlinepathogenesis. In order to counteract the advancement of this disease, a possible therapeutic avenue is to curb the newlinemisfolding and aggregation of hIAPP. Within this thesis, we embark on the intricate journey of hIAPP aggregation, newlinecoupled with the myriad classes of compounds harboring the potential to impede this process. In Chapter I, a newlinefoundation is laid through the introduction of hIAPP and an array of different categories of inhibitors, each contributing newlineto the modulation of hIAPP aggregation. A brief discussion of the molecular dynamics simulation methodology, which newlineis a vital framework underpinning our study is followed. Thereafter, Chapter II takes the helm into venturing the newlinedifferent conformational states of an amyloid prone fragment of hIAPP, hIAPP20-29, via Markov State Modelling. Here, newlinethe transition pathway between the metastable states is analysed, which are crucial for the misfolding of hIAPP. newlineChapter III explores the influence of two small biological molecules on hIAPP aggregation. In Part (a), we have newlineexplored the effect of norepinephrine, which is a common neurotransmitter, on the amyloidogenesis of hIAPP. In Part newline(b), a new aspect of adenosine triphosphate (ATP), other than being the energy source for biochemical processes, is newlineinquired. This chapter, thus, enlighten us about the diversity of the molecular structures that can modulate the newlineaggregation of hIAPP and the effect of these structures on the activity of the inhibitors. Chapter IV turns the discourse newlinetowards peptides and peptidomimetics, probing their roles in shaping the aggregation narrative. Two such inhibitors newlineare investigated, both of which are extracted from the amyloid core region of hIAPP, i.e., N22FGAIL27. In Part (a), this newlinehIAPP fragment is replaced with all D-amino acids, and is used to prohibit the self-assembly of full-length hIAPP. In newlinePart (b), a conformationally restricted element, aminobenzoic acid is incorporated into