LAWS: Local alignment for water sites-Tracking ordered water in simulations

Area of Science:

• Computational biology
• Structural biology
• Biophysics

Background:

• Accurate modeling of protein-water interactions is crucial for understanding protein function via molecular dynamics (MD) simulations.
• Crystallographic water sites (CWS) from X-ray crystallography can validate MD simulations, but require methods accounting for protein dynamics.
• Existing CWS analysis methods using global protein alignment introduce errors with significant structural deviations.

Purpose of the Study:

• To develop and validate a novel method for analyzing crystallographic water sites (CWS) in molecular dynamics (MD) simulations.
• To overcome limitations of global alignment methods in comparing CWS between crystal structures and MD simulations.
• To assess the stability and conservation of CWS in protein crystals and solution simulations.

Main Methods:

• Introduced the local alignment for water sites (LAWS) method, inspired by GPS multilateration.
• LAWS utilizes interaction distances between CWS and protein atoms from crystal structures to track CWS in simulations.
• Applied LAWS to MD simulations of a protein in both crystal and solution environments.

Main Results:

• LAWS identified CWS with higher water density and less perturbed protein environments compared to existing methods.
• All high-confidence CWS were preserved in the crystal simulations, highlighting the importance of crystal packing.
• A common set of CWS was identified in both crystal and solution simulations, located in pockets and coordinated by residues within the same domain.

Conclusions:

• The LAWS algorithm provides a more accurate and robust method for analyzing CWS in MD simulations.
• LAWS demonstrates the significant role of crystal packing in maintaining CWS stability.
• The identified conserved CWS suggest LAWS is valuable for studying ordered water molecules and water networks in general.