Exploring the influence of water micro assemblies on protein folding, enzyme catalysis and membrane dynamics

Abstract

Water is central to biological processes not only as a solvent, but also as an agent shaping macromolecular behavior. Insights into water micro assemblies (WMA), defined by transient regions of low-density water (LDW) and high-density water (HDW), have highlighted their potential impact on biological phenomena. LDW, with its structured hydrogen bonding networks and reduced density, stabilizes hydrophobic interfaces and promotes ordered molecular configurations. Conversely, HDW, with its dynamic and flexible nature, facilitates transitions, solute mobility and molecular flexibility. By correlating experimental observations with simulations, we explore the influence of WMA on three key biological processes. In protein folding, LDW may stabilize hydrophobic cores and secondary structures by forming structured exclusion zones, while HDW may introduce dynamic flexibility, promoting the resolution of folding intermediates and leading to dynamic rearrangements. In enzyme catalysis, LDW may form structured hydration shells around active sites stabilizing active sites over longer timescales, while HDW may support substrate access and catalytic flexibility within active sites. In membrane dynamics, LDW may stabilize lipid headgroups, forming structured hydration layers that enhance membrane rigidity and stability, while HDW may ensure the nanosecond-scale flexibility required for vesicle formation and fusion. Across these tree processes, the WMA’s energy contributions, timescales and spatial scales align with the forces and dynamics involved, highlighting the role of LDW and HDW in modulating cellular interactions. This perspective holds implications for the design of lab-on-chip devices, advancements in sensor technologies, development of biomimetic membranes for drug delivery, creation of novel therapeutics and deeper understanding of protein misfolding diseases.