OPEP6: A New Constant-pH Molecular Dynamics Simulation Scheme with OPEP Coarse-Grained Force Field

Area of Science:

• Computational chemistry
• Biophysics
• Molecular modeling

Background:

• Accurate modeling of pH effects on biomolecules is crucial for understanding molecular processes.
• Rigid titration models have limitations in capturing the interplay between molecular conformation and acid-base equilibrium.
• Atomistic simulations face convergence issues, necessitating coarse-grained approaches.

Purpose of the Study:

• To introduce a novel coarse-grained protocol, OPEP6, for constant-pH molecular dynamics simulations.
• To enhance the description of electrostatic and structural properties of biomolecules under varying pH conditions.
• To overcome sampling difficulties and reduce computational costs associated with molecular simulations.

Main Methods:

• Coupling the OPEP force field for proteins with a fast proton titration scheme.
• Utilizing coarse-grained modeling to address sampling challenges.
• Benchmarking OPEP6 using a set of representative proteins (HP36, BBL, HEWL, NTL9, and a protein G variant).

Main Results:

• OPEP6 achieved average, maximum absolute, and root-mean-square deviations of [0.3-1.1], [0.6-2.5], and [0.4-1.3] pH units for pKa values across five proteins, respectively.
• Calculated pKa values showed improved accuracy compared to rigid models and aligned well with experimental data, particularly for BBL.
• Structural properties of insulin, tested at different pH conditions, were accurately reproduced, agreeing with crystallographic data.

Conclusions:

• The OPEP6 protocol effectively models pH-mediated effects in biomolecules, offering improved accuracy and efficiency.
• This coarse-grained approach enhances the study of electrostatic and structural properties relevant to biological processes.
• OPEP6 provides a powerful tool for future investigations into pH-dependent biological mechanisms.