Biomolecular recognition mechanisms studied by NMR spectroscopy and MD simulations

Abstract

This thesis describes the use of solution Nuclear Magnetic Resonance (NMR) spectroscopy and Molecular Dynamics (MD) simulations to study the mechanism of biomolecular recognition with two model systems: i) lipid II-binding lantibiotics (lanthionine-containing antibiotics) and ii) the human immunodeficiency virus 1 (HIV-1) envelope protein (Env), gp120, and its receptor molecule, CD4. The first system concerns a group of unique antimicrobial peptides, which make use of an hitherto unknown mechanism of attacking bacteria by targeting the Achilles¹ heel of bacteria, the cell wall precursor, lipid II. In the light of antibiotic resistance, understanding of this recognition mechanism may lead to novel antibiotics. The second system focuses on the initiation step of the HIV-1 viral entry wherein the engagement of gp120 and CD4 switches on a cascade of conformational changes that are necessary for the membrane fusion between the virus and the host cell. The biological contexts of both systems are important to human health and numerous functional studies on both systems have been well documented. Yet, because of the underlying dynamics and the intricate assembly process of higher order complexes, a detailed structural description is currently lacking in both systems. We therefore applied advanced NMR and MD techniques to unravel the structure and dynamics of these complexes with the hope to facilitate the development of new antibiotics and vaccines for infectious diseases, such as AIDS. As biological functions are manifested by interactions at a molecular level, understanding of structural properties of these biomolecules may consolidate related biomedical research.