Constant pH molecular dynamics with proton tautomerism.

Area of Science:

• Computational Chemistry
• Molecular Dynamics
• Biophysics

Background:

• Proton tautomerism is crucial for protein function and requires accurate simulation methods.
• Continuous constant pH molecular dynamics (CPHMD) is a powerful technique for studying pH-dependent phenomena.
• Existing CPHMD methods have limitations in accurately modeling proton tautomerism.

Purpose of the Study:

• To develop and validate a new two-dimensional lambda-dynamics method for CPHMD simulations.
• To incorporate proton tautomerism of carboxyl and histidine residues into CPHMD.
• To assess the accuracy of the new method in predicting pKa values and pH-coupled dynamics.

Main Methods:

• Developed a two-dimensional lambda-dynamics framework for tautomeric state titration.
• Integrated the method with GBSW implicit solvent model for CPHMD simulations.
• Tested the method on model systems (histidine, aspartic acid) and benchmark proteins (OMTKY3, RNase A).

Main Results:

• Achieved average absolute errors of 1.0 pK unit in OMTKY3 and 1.6/0.6 pK units for carboxyl/histidine in RNase A.
• Successfully predicted the sign of pKa shifts for benchmark proteins.
• Validated tautomeric and conformational state predictions against experimental data for specific histidine residues.

Conclusions:

• The new 2D lambda-dynamics method enhances CPHMD simulations by accurately including proton tautomerism.
• The method demonstrates capability in revealing pH-coupled conformational dynamics of protein side chains.
• This advancement improves the prediction of pKa values and protein behavior under varying pH conditions.