Hydration dynamics at biologically relevant interfaces: A nano-scale investigation based on molecular dynamics simulations

Ghosh, Brataraj (2023) Hydration dynamics at biologically relevant interfaces: A nano-scale investigation based on molecular dynamics simulations. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Brataraj Ghosh (14IP014)) 14IP014.pdf - Submitted Version Restricted to Repository staff only Download (3MB)

Abstract

This thesis, titled ‘Hydration dynamics at biologically relevant interfaces: A nanoscale investigation based on molecular dynamics simulations’ is a computational study of the structural and dynamical behavior of interfacial water at varying nature of biologically relevant nanoscale surfaces. In recent times, novel experimental methods have been developed to probe the interactions and pathways in determining the underlying complexity in hydration dynamics and biomolecular behavior. To a large extent, computational methods are capable of providing a direct, molecularlevel picture. In this work, fully atomistic molecular dynamics (MD) simulations were applied to investigate the underlying regulatory principles and the critical dependence of the hydration slaving phenomenon at different physio-chemical surfaces. Properties of water under nano-confinement, analogous to the water flow within biological channels, are studied using artificial channels created with single-walled carbon nanotubes (SWNT) and graphene sheets. investigations focus on delineating structural and dynamical properties of nano-confined water in presence of co-solvents with reduced polarity (hexafluoro-2-propanol or HFIP). We observed the average flow rate decreases with increasing nano-channel length when the HFIP intrusion number is lower. For the number of confined HFIPs exceeding this number, the flow shows little variation, if any, with length. In light of emerging insights into the mechanistic aspects of solvent permeability across channels, our study will be helpful to devising ways of modulating solvent properties within nano-channels with cosolvent impurities. Next we investigated the effect of glucose as a molecular crowder on the solvent environment in proximity of the protein surface in putative folded (Ubiquitin) and intrinsically disordered (dimeric Amyloid beta) states. Studying the physical effects of glucose crowding mediated purterbation of interfacial water on the early self-assembly (dimerization) of the Aβ peptide is crucial; not only due to reported correlation between type-2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) but also to put up a comparison between the response of an IDP dimer and a folded globular protein due to crowding mediated perturbation of interfacial water. Atomistic simulations reveal markedly higher structural perturbation in the disordered systems due to crowding effects, while the folded state retains overall structural fidelity. Key hydrophobic contacts in the disordered dimer are lost. However, glucose induced crowding results in elevated hydration on surfaces of both protein systems. Despite evident differences in their structural responses, the hydration layer of both the folded and disordered states display a distinct enhancement in lifetimes of mean residence and rotational relaxation under the hyperglycemic conditions. Lastly, we also focused on hydration mediated transition of DNA double helix from less hydrated A conformation to a well hydrated biologically more prevalent canonical B conformation in a sequence dependant manner. The A -form is induced when protein or any ligand molecule interact or bind with B-form DNA. We restrained A conformation which is unstable in aqueous solution and observed dynamical behaviour of interfacial water around the sugar-phosphate backbone, major and minor groove. The observation reveals that dynamical behavior of water, particularly around the groove regions are opposite between the two above mentioned conformations; regardless the sequences considered. The study will be helpful to elucidate the mediation role hydration water plays in interaction with DNA and other macro-molecules. The thesis is divided into six chapters are described below. Chapter 1: In the introductory chapter, the anomalous nature of water and its relevance in biological context have been briefly discussed. The association of proteins and DNA with the surrounding solvent environment, and how solvent mediated physico-chemical processes are important in biology are discussed. Chapter 2: An overview on the scope of computations in atomic level understanding, the theory behind atomistic molecular dynamics simulations, control of thermodynamic parameters in MD, analyses protocols are been briefly elaborated. Chapter 3: This chapter aims on investigating the solvent properties within hydrophobic nano-channels that can be considered analogous to biological ion channels are briefly elaborated. Chapter 4: This section discusses the effect of glucose as a molecular crowder on the solvent environment perturbation in proximity to intrinsically disorded IDP dimer (amyloid beta) and a folded globular protein (ubiquitine). Chapter 5: Study related to hydration mediated conformational transition of DNA double helix along with the dynamical behaviour of interfacial water around different DNA conformation is scrutinized here. Chapter 6: Future perspectives in relation to continuing studies are discussed.

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