Study of Structure and Dynamics of Bioactive Natural and Synthetic Peptides by NMR Spectroscopy and In silico Methods

Abstract

The thesis covers conformational analysis of several bioactive peptides using solution and solid-state NMR along with in silico analysis of some of them compiled in five chapters. It starts with an introduction to solution and solid-state NMR along with basics of peptides/ proteins and in silico methods in chapter 1. Chapter 2 covers work carried out on conformational analysis of Glutathione oxidized (GSSG) molecule investigated through solution NMR which suggests an antiparallel structure with different hydrogen bonding pattern and includes a comparison of the results obtained earlier in the solid-state NMR. In addition, influence of pH alterations on GSSG conformation is also reported which indicate GSSG to sample a broad range of conformational space depending on its surrounding environment. Chapter 3 discusses the structure elucidation of the missing central part of AICD (Amyloid precursor protein Intra Cellular Domain) 12 residue fragment along with in silico analysis of the whole stretch incorporating the newly determined central stretch. It also covers metal and polyphenol interactions with the AICD16-27 peptide indicating Histidines to be more prone for interaction. Chapter 4 deals with conformational analysis of Selenocysteine peptides where Selenium replaces the Sulphur atom in the amino acid Cysteine. An analysis based on 1- and 2-dimensional solid-state NMR spectra have been made suggesting multiple conformations in a unit cell and complementary DFT calculations are also given. Finally in chapter 5, N-terminal A-beta fragments structure comparison is carried out as fragment size increases along with metal and polyphenol interactions which indicate involvement of aromatic and charge residues. Hence it is useful to understand the aggregation effects leading to fibril formation in Alzheimer s disease. Overall, the studies aim at understanding bioactive peptide conformations which may help in drug discovery for prevention of various diseases.