Efficient free energy calculations by combining two complementary tempering sampling methods.

Area of Science:

• Computational Chemistry
• Molecular Dynamics Simulations
• Statistical Mechanics

Background:

• Reaction coordinate (RC) guided sampling methods efficiently cross high energy barriers but struggle with identifying correct RCs or handling high dimensionality.
• Hidden energy barriers in other degrees of freedom (DOFs) can lead to insufficient sampling in simulations.

Purpose of the Study:

• To address the challenge of insufficient sampling caused by hidden energy barriers in molecular simulations.
• To introduce and evaluate a novel hybrid method combining TAMD and ITS for enhanced sampling.

Main Methods:

• Developed a combined Integrated Tempering Sampling-Temperature Accelerated Molecular Dynamics (ITS-TAMD) method.
• TAMD guides sampling along major RCs with high barriers, while ITS enhances sampling in other DOFs with lower barriers.
• Tested the ITS-TAMD method on three systems exhibiting hidden barrier phenomena.

Main Results:

• Achieved at least a five-fold improvement in sampling efficiency compared to standalone TAMD or ITS, even with hidden energy barriers.
• Demonstrated more accurate recovery of the canonical distribution, enabling correct computation of thermodynamic properties.
• Showcased robustness in major RC selection, suggesting a reduction in the required dimensionality of RCs.

Conclusions:

• The ITS-TAMD method offers a powerful and efficient tool for molecular simulations, particularly for systems with hidden energy barriers.
• This hybrid approach improves sampling efficiency, accuracy of thermodynamic property calculations, and reduces the complexity of RC selection.
• The ITS-TAMD method has broad potential applications for investigating complex molecular processes.