Biomolecular free energy profiles by a shooting/umbrella sampling protocol, "BOLAS"

Area of Science:

• Computational chemistry
• Biomolecular simulations
• Statistical mechanics

Background:

• Calculating free energy profiles for conformational transitions in complex systems is computationally challenging.
• Traditional methods like force-biased umbrella sampling can introduce systematic errors.
• Accurate free energy calculations are crucial for understanding biomolecular mechanisms.

Purpose of the Study:

• To develop an efficient and accurate computational technique for determining free energy profiles of conformational transitions.
• To introduce a novel method, BOLAS (Biased Over-sampling with a Lasso-like Algorithm Scheme), that combines Monte Carlo and umbrella sampling.
• To reduce systematic errors in free energy calculations for complex biomolecular systems.

Main Methods:

• The BOLAS method combines a Monte Carlo ensemble of trajectories generated by the shooting algorithm with umbrella sampling.
• It is motivated by transition path sampling and preserves microscopic reversibility.
• The method ensures the correct equilibrium distribution is achieved.

Main Results:

• BOLAS demonstrates validity for a bistable potential, accurately computing free energy profiles.
• The method shows lower systematic error compared to traditional force-biased umbrella sampling protocols.
• An application to the sugar repuckering transition in solvated deoxyadenosine illustrates the method's scope.

Conclusions:

• BOLAS provides an efficient and accurate approach for computing free energy profiles of conformational transitions in complex systems.
• The method offers a significant improvement over traditional techniques, particularly for biomolecular systems.
• BOLAS has broad applicability in studying molecular mechanisms and conformational dynamics.