Date of Award
6-26-2026
Date Published
July 2026
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical and Chemical Engineering
Advisor(s)
Shikha Nangia
Subject Categories
Chemical Engineering | Engineering
Abstract
Hydropathy — the distinction of hydrophobic, hydro-neutral and hydrophilic character at the residue level — governs local hydration, interfacial energetics, and molecular stability across diverse biomolecular systems, yet a unified, quantitative framework for characterizing these interactions has long been lacking. Molecular dynamics (MD) simulation, which models the time evolution of atomic systems by numerically integrating Newton's second law of motion for every atom at each timestep, provides the atomistic resolution necessary to capture environment-dependent hydration behavior that fixed residue-based scales cannot represent. Forces are derived from classical potential energy functions describing bonded and non-bonded interactions, and iterative integration of these forces generates trajectories encoding protein conformational fluctuations, water reorganization, lipid remodeling, and DNA dynamics at timescales relevant to biological function. The Protocol for Assigning a Residue's Character on a Hydropathy (PARCH) scale leverages MD thermal annealing trajectories to quantify hydropathy in a topography and environment-sensitive manner, and has been extended across three fundamentally distinct biological contexts. In isolated nucleic acids, PARCH reveals a clear and quantitative distinction between nucleobase and backbone hydropathy, with the sugar–phosphate backbone exhibiting hydrophilicity approximately an order of magnitude greater than that of the bases, establishing a physicochemical baseline for DNA and RNA that is modulated by molecular context. In chromatin, PARCH applied to nucleosome structures spanning multiple species, a dinucleosome assembly, and an epigenetically methylated state demonstrates that histone association selectively reshapes DNA backbone hydropathy while leaving nucleobase hydropathy invariant, that conserved arginine anchors act as primary physicochemical mediators of DNA compaction, that higher-order dinucleosome formation reduces backbone hydrophilicity selectively at buried inter-nucleosomal interfaces, and that cytosine methylation decreases backbone hydrophilicity through propagation of a localized nucleobase perturbation. In membrane proteins, a lipid-shell modification to PARCH imposes the correct chemical potential boundary condition for transmembrane residues, reproducing the hydrophobic-to-hydrophilic ordering of all twenty amino acids at the bilayer midplane, recapitulating depth-dependent hydration profiles, and revealing per-residue cooperative hydration redistribution in a double arginine variant of OmpLA — providing microscopic mechanistic insight that bulk thermodynamic measurements alone could not supply. Together, these results establish hydropathy quantified through MD simulation as a universal and broadly applicable principle of biomolecular organization, spanning nucleic acids, chromatin, and lipid-embedded transmembrane proteins.
Access
Open Access
Recommended Citation
Mandal, Ratnakshi, "Development of PARCH hydropathy scale to study nucleic acids, nucleosomes, chromatin organization and transmembrane proteins" (2026). Dissertations - ALL. 2317.
https://surface.syr.edu/etd/2317
