Water structure theory and some implications for drug design.

Area of Science:

• Physical Chemistry
• Biophysics
• Materials Science

Background:

• Historically, experimental measurement challenges hindered water structure theories.
• Recent advancements in measurement and computer modeling have led to converging theoretical models of water structure.
• Current understanding views water as a mixture of randomly hydrogen-bonded molecules and stable, aggregated tetrahedral structures.

Purpose of the Study:

• To present a converging model of water structure based on recent experimental and computational findings.
• To explore the implications of this refined water structure model for understanding molecular interactions in biological systems.
• To re-evaluate the concept of "associated water" in biological contexts.

Main Methods:

• Review of experimental studies on ices, clathrates, and liquid solutions.
• Analysis of computer modeling studies on water structure.
• Integration of evidence from various sources to support a unified model.

Main Results:

• Water is a mixture of transient and stable hydrogen-bonded structures, including ring aggregates and cage-like motifs.
• Specific structures, like the (H2O)20 cavity, exhibit high stability and recur across different systems.
• Solute interactions with water can induce secondary hydration shells, influencing molecular recognition and biomolecular conformation.

Conclusions:

• A non-continuum model of water is essential for accurately simulating aqueous solutions and biological interactions.
• The "associated water" concept, where water structure around solutes differs from bulk, warrants reappraisal.
• Bioactive ligands may modulate protein conformation through selective interactions with water structures, similar to structure-making/breaking solutes.