Constant pH Molecular Dynamics in Explicit Solvent with Enveloping Distribution Sampling and Hamiltonian Exchange

Area of Science:

• Computational Chemistry
• Biophysical Chemistry
• Molecular Dynamics

Background:

• Constant pH simulations are crucial for understanding biomolecular behavior.
• Existing methods using continuous charge models have limitations.
• Accurate modeling of discrete protonation states is essential.

Purpose of the Study:

• To introduce a novel computational approach for constant pH simulations in explicit solvent.
• To combine enveloping distribution sampling (EDS) and Hamiltonian replica exchange (HREX) for enhanced accuracy.
• To accurately model discrete protonation states and calculate pKa values.

Main Methods:

• Utilized enveloping distribution sampling (EDS) to generate hybrid Hamiltonians of different protonation states.
• Employed Hamiltonian replica exchange (HREX) with varying smoothness parameters (s) to facilitate state transitions.
• Performed simulations in explicit solvent, analyzing ensembles from EDS Hamiltonians without smoothing (s = ∞).

Main Results:

• The EDS-HREX method accurately predicts pKa values for systems with 2 to 8 protonation states.
• Mean absolute errors for small systems were 0.03–0.17 pKa units.
• Errors for snake cardiotoxin's titratable groups ranged from 0.2–1.6 pKa units, showing good agreement with experimental data.

Conclusions:

• EDS-HREX provides a potent theoretical framework for constant pH simulations.
• The method accurately describes multiple protonation states.
• Achieved good calculated pKa values, demonstrating the approach's efficacy.