Using Selectively Applied Accelerated Molecular Dynamics to Enhance Free Energy Calculations

Area of Science:

• Computational chemistry
• Biomolecular simulations
• Molecular dynamics

Background:

• Accelerated molecular dynamics (aMD) enhances sampling but faces challenges in accurate free energy calculations due to reweighting issues.
• Classical molecular dynamics (MD) can be computationally expensive for exploring complex conformational landscapes.

Purpose of the Study:

• To introduce and validate a novel selective accelerated molecular dynamics (aMD) method.
• To improve the efficiency and accuracy of free energy calculations in biomolecular systems.

Main Methods:

• Development of selective aMD, focusing acceleration on pertinent degrees of freedom.
• Simulation of alanine dipeptide using classical MD, all-dihedral aMD, and selective aMD.
• Calculation of free energy for oseltamivir decoupling in neuraminidase using selective aMD.

Main Results:

• Selective aMD and all-dihedral aMD both improved free energy landscape convergence by 5-fold compared to classical MD.
• Selective aMD yielded superior statistics and more reliable free energy estimates than all-dihedral aMD.
• Selective aMD significantly reduced the computational cost for alchemical free energy transformations.

Conclusions:

• Selective aMD offers a more robust and efficient approach for free energy calculations in complex biomolecular systems.
• The method addresses the reweighting limitations of traditional aMD, improving statistical accuracy.
• Selective aMD is particularly beneficial for pharmaceutically relevant alchemical free energy transformations.