Decoding determinants of selectivity in biomolecules

Abstract

Molecular events demonstrate remarkable specificity amid complexity in its cellular environment. This phenomenon, termed biomolecular recognition, is fundamental to the organization and regulation of biological systems. Deciphering how such precise interactions emerge, despite the seemingly chaotic milieu, remains a central question in molecular biophysics. Selectivity arises from a fine interplay of molecular and environmental factors. On the one hand, physico-chemical determinants such as shape complementarity, electrostatics, stereochemistry, and solvation define structural compatibility. On the other hand, contextual and dynamic factors, including conformational flexibility, molecular crowding, kinetic accessibility, and allosteric regulation shift preferences in response to environmental cues. This thesis explores different facets of selectivity through three different biomolecular systems but converges on a unifying theme: synergy between the molecule’s structure and dynamics in a crowded environment. Project 1 investigates how post-translational glycosylation regulates protein dynamics and ligand selectivity through allosteric effects and hydration shell modulation, using the Lili-Mip lipocalin as a model. Project 2 examines how lipid phase heterogeneity gives rise to transient dynamic pathways in membranes, selectively enabling encounters of membrane-associated molecules within otherwise ordered domains. Project 3 explores how synthetic oligomers with engineered sequence and structural features achieve selective targeting and disruption of biological membranes, exploiting principles of molecular crowding and kinetic accessibility. This thesis works with molecular dynamics (MD) simulations as a central tool to probe nano- and meso-scale dynamics of these phenomena that are often inaccessible by experiments. MD simulations allow the exploration of conformational landscapes, hydration dynamics, and collective motions with atomistic detail, offering insights into the origins of selectivity beyond the temporal and spatial resolution of most experiments. By dissecting selectivity across these diverse yet connected systems, this thesis contributes to a deeper understanding of how biomolecular recognition is orchestrated at the molecular level.