Boosting the conformational sampling by combining replica exchange with solute tempering and well-sliced metadynamics

Area of Science:

• Computational Chemistry
• Molecular Dynamics Simulations
• Biophysics

Background:

• Enhanced sampling techniques are crucial for studying large, soft molecular systems with complex energy landscapes.
• Combining collective variable (CV) based enhanced sampling with global tempering methods can accelerate conformational sampling and free energy calculations.
• Existing methods face challenges in efficiently sampling slow degrees of freedom in complex systems.

Purpose of the Study:

• To propose and validate a new hybrid enhanced sampling method integrating well-sliced metadynamics (WSMTD) with replica exchange with solute tempering (REST2).
• To improve the efficiency of conformational sampling and free energy calculations for large and soft molecular systems.
• To enable boosted sampling of slow degrees of freedom without explicit CV specification.

Main Methods:

• A novel hybrid method combining WSMTD and REST2 is developed.
• WSMTD utilizes a divide-and-conquer strategy for sampling high-dimensional free energy surface slices.
• REST2 facilitates replica exchange to enhance sampling of slow degrees of freedom within WSMTD simulations.
• The weighted histogram analysis method (WHAM) is used to combine probability distributions and reconstruct the free energy surface.

Main Results:

• The proposed hybrid WSMTD-REST2 method demonstrates accuracy and improves conformational sampling.
• The method achieves rapid convergence in free energy estimates.
• Successful application in computing conformational free energy landscapes of solvated alanine tripeptide and Trp-cage mini protein in explicit water.

Conclusions:

• The hybrid WSMTD-REST2 method effectively accelerates molecular simulations for complex systems.
• This approach offers a powerful tool for accurate free energy calculations and conformational landscape exploration.
• The method shows significant potential for studying biomolecular systems with numerous energy minima.