Improving Speed and Affordability without Compromising Accuracy: Standard Binding Free-Energy Calculations Using an...

Area of Science:

• Computational chemistry and molecular dynamics simulations.
• Biophysics and structural biology.
• Pharmacology and drug discovery.

Background:

• Accurate in silico protein-ligand binding free energy evaluation is crucial for drug design.
• The geometrical route using well-tempered metadynamics extended adaptive biasing force (WTM-eABF) provides reliable binding affinity calculations.
• Current WTM-eABF methods are computationally expensive, requiring significant simulation time for convergence.

Purpose of the Study:

• To enhance the efficiency of the geometrical route for binding free energy calculations.
• To maintain the reliability and ergodic sampling of the WTM-eABF method.
• To identify optimal simulation parameters for accelerated convergence.

Main Methods:

• Combining hydrogen-mass repartitioning (HMR) for a longer integration time step with multiple time-stepping (MTS) for collective-variable and biasing-force evaluation.
• Performing numerous WTM-eABF simulations with varying HMR, MTS schemes, and enhanced-sampling parameters for the Abl kinase-SH3 domain:p41 complex.
• Validating the optimized method on the MDM2-p53:NVP-CGM097 complex.

Main Results:

• An optimal set of parameters was identified, accelerating simulation convergence by a factor of three.
• The enhanced method demonstrated no noticeable loss of accuracy compared to standard approaches.
• The optimized protocols showed transferability to different protein-ligand complexes.

Conclusions:

• The developed computational strategy significantly improves the efficiency of binding free energy calculations.
• This advancement facilitates more rapid and cost-effective drug design and discovery processes.
• The findings offer a more practical approach for utilizing WTM-eABF in computational drug development.