An efficient protocol for computing the pK_a of Zn-bound water

Area of Science:

• Computational Chemistry
• Biochemistry
• Structural Biology

Background:

• Determining the protonation state of metal-bound water is essential for understanding pH-dependent biological processes.
• Existing methods for predicting protonation states are insufficient for metal complexes, particularly zinc (Zn2+).

Purpose of the Study:

• To develop and validate efficient and accurate computational methods for predicting the absolute pKa values of metal-bound water (pKw) in Zn2+-complexes.
• To provide a tool for evaluating Zn2+ coordination sites in proteins and understanding factors influencing pKw.

Main Methods:

• Tested 18 geometry optimization methods on 19 high-resolution Zn2+ complex structures.
• Evaluated 98 methods for reproducing 36 experimental pKw values of diverse Zn2+ complexes.
• Focused on accurate estimation of Zn2+-bound water/hydroxide solvation.

Main Results:

• Identified optimized computational protocols for geometry optimization and pKw prediction of Zn2+-complexes.
• Demonstrated the critical importance of solvation estimation for accuracy.
• Found basis set superposition error correction to be non-essential for these calculations.

Conclusions:

• The presented protocol enables accurate prediction of Zn2+-bound water pKw values.
• This tool can assess Zn2+ sites in proteins and elucidate factors controlling water deprotonation.
• Accurate pKw prediction offers insights into enzyme mechanisms and facilitates the design of metal-binding drugs.