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Disputation Honey Ashok Jain

11.03.2024 | 14:00
Thema der Dissertation:
Networks of influence: Water mediated hydrogen bond networks at anionic lipid interfaces and Hv1 proton channel
Abstract: Dynamic hydrogen-bonds (H-bonds) and H-bond networks govern essential biomolecular process. From providing conformational flexibility needed for the functioning of proteins, governing the fluidity, stability and permeability of cell membranes to serving as proton transfer pathways, H-bonds are observed abundantly in nature. It is thus crucial to understand the dynamics of H-bond networks in biological systems to guide drug discovery. In this thesis, I focus on characterizing and identifying the dynamic H-bond networks in mainly two biomolecular systems - (i) lipid membranes containing anionic lipids and (ii) Human voltage gated proton channel Hv1. I use atomistic molecular dynamics simulations along with graph theory based approach for efficient computations of dynamic H-bonds and H-bond networks of proteins and lipid membranes.
At the lipid bilayer interface, dynamic H-bonding can give rise to local lipid clusters of interest for reactions. The dynamics of these H-bonded lipid clusters can depend on the nature of lipid headgroups. To dive deeper into role of lipid headgroups in H-bonded lipid clusters, I use a previously developed graph theory based approach to analyze the topology of lipid clusters in zwitterionic and anionic lipid membranes including bacterial cell membranes. To understand the dynamics of anionic membranes, I further do a topology analysis of bilayers of phosphatidylserine containing varying concentrations of cholesterol. I find that presence of cholesterol can hinder the formation of extended water-mediated H-bond networks in phosphatidylserine membranes.
H-bond networks formed by clusters of carboxylate and histidine protein sidechains or anionic lipid headgroups can form pathways for proton transfer across and along the lipid membranes. To understand the functioning mechanism of proton transporters, it is crucial to identify and characterize these proton-binding clusters and the H-bond pathways between them. To this aim, I developed a graph theory based protocol to find the most frequently sampled water-mediated H-bond paths formed by titratable sidechains of transmembrane proteins and/or lipid headgroups. I implement this protocol to identify potential proton antennas of the human voltage gated proton channel Hv1. The functioning of Hv1 is regulated by a network of H-bonds formed between the titratable sidechains of the transmembrane protein. How does the pH and lipid composition of the membrane affects the H-bond network of Hv1 remains an open question. I apply the newly developed protocol to study the protonation-coupled and lipid-coupled H-bond dynamics of Hv1. I find that depending on the location of the protonated carboxylate or histidine, the H-bond network extends or collapses on either the intracellular or extracellular side. A continuous H-bond network spanning the proton channel is sampled only in phosphatidylserine bilayer in contrast to bacterial and zwitterionic bilayers. This suggest the role of lipid composition in regulating the H-bond network dynamics of Hv1. In this thesis, I also present the work done towards characterizing the impact of Hv1 inhibitors on H-bond networks of Hv1.

Zeit & Ort

11.03.2024 | 14:00