Consensus preferred hydration sites in six FKBP12-drug complexes

Area of Science:

• Structural Biology
• Computational Chemistry
• Biophysics

Background:

• Understanding protein hydration is crucial for drug discovery and molecular modeling.
• The FK506-binding protein 12 (FKBP12) is a key target in various therapeutic areas.
• Accurate prediction of water molecule interactions with proteins remains a challenge.

Purpose of the Study:

• To derive a consensus set of hydration sites for the FKBP12 protein.
• To evaluate the utility of these consensus sites in improving hydration prediction algorithms.
• To establish a foundation for theoretical analyses of protein hydration properties.

Main Methods:

• Comparative analysis of water molecules across six FKBP12-drug complex crystal structures.
• Identification of consensus hydration sites, including buried water and protein-contacting sites.
• Assessment of two hydration prediction algorithms (AUTO-SOL and AQUARIUS2) using the consensus sites.

Main Results:

• A refined set of consensus hydration sites for FKBP12 was identified.
• The consensus sites significantly enhanced the apparent efficacy of AUTO-SOL and AQUARIUS2.
• Buried water molecules were consistently included in the consensus set.
• No unique features distinguished consensus sites from discarded sites without multi-crystal comparisons.

Conclusions:

• The proposed consensus hydration sites provide a more accurate representation of FKBP12 hydration in solution.
• This consensus approach improves the performance of hydration prediction tools.
• Comparative structural analysis is essential for robust hydration site identification and theoretical studies.