Replica Exchange Gaussian Accelerated Molecular Dynamics: Improved Enhanced Sampling and Free Energy Calculation

Area of Science:

• Computational Chemistry
• Biophysics
• Molecular Dynamics

Background:

• Gaussian accelerated molecular dynamics (GaMD) enhances sampling and free energy calculations for biomolecules.
• GaMD achieves this by smoothing the potential energy surface with a harmonic boost potential, eliminating the need for predefined reaction coordinates.
• Further improvements are sought to enhance GaMD's acceleration power and energy reweighting capabilities.

Purpose of the Study:

• To improve the acceleration power and energy reweighting of GaMD by integrating it with replica exchange algorithms.
• To introduce and evaluate two novel versions of replica exchange GaMD (rex-GaMD): force constant rex-GaMD and threshold energy rex-GaMD.
• To assess the effectiveness of rex-GaMD in enhancing conformational transitions and enabling accurate free energy calculations.

Main Methods:

• Developed two replica exchange GaMD (rex-GaMD) variants: force constant rex-GaMD and threshold energy rex-GaMD.
• Force constant rex-GaMD exchanges boost potentials between replicas with varying harmonic force constants but a fixed threshold energy.
• Threshold energy rex-GaMD switches the threshold energy between bounds to generate diverse boost potentials.

Main Results:

• Simulations on alanine dipeptide, chignolin, and HIV protease demonstrated enhanced conformational transitions using rex-GaMD.
• The continuous exchange of boost potentials in rex-GaMD narrowed the distribution width of applied boost potential.
• This narrowing facilitates accurate energetic reweighting, enabling the recovery of biomolecular free energy profiles.

Conclusions:

• The integration of GaMD with replica exchange algorithms significantly enhances molecular dynamics simulations.
• Both force constant and threshold energy rex-GaMD methods effectively improve sampling and free energy calculations.
• rex-GaMD provides a powerful approach for studying biomolecular conformational dynamics and energetics.