Druglike Molecules Binding to Large Membrane Proteins: Absolute Binding Free Energy Computation

Area of Science:

• Computational chemistry
• Biophysics
• Structural biology

Background:

• Integral transmembrane proteins like SERCA (Ca2+-ATPase) are vital drug targets.
• Their large size poses significant computational challenges for drug discovery.
• Accurate prediction of binding free energy is crucial for drug development.

Purpose of the Study:

• To calculate the standard binding free energy of BHQ and its analogs to SERCA.
• To assess the impact of para-alkyl group additions on binding affinity.
• To validate computational methods against experimental binding data.

Main Methods:

• Employed alchemical double-decoupling with restraining potentials and the FEPMD method.
• Integrated Generalized Born and spherical solvent boundary potential methods for implicit solvent treatment.
• Separately computed contributions from electrostatic, repulsive, dispersive, and restraining potentials.

Main Results:

• The calculated binding free energy for BHQ (11.63 kcal/mol) closely matched experimental values (10.56 kcal/mol).
• Accurate binding free energy was predicted for the analog with one para-methyl group.
• Discrepancies were observed for analogs with two and three para-methyl groups, with convergence issues for the latter.

Conclusions:

• The computational approach shows promise for predicting binding free energies of drug-like molecules to transmembrane proteins.
• Further refinement of methods is needed to accurately capture the effects of bulky substituents on binding affinity.
• Challenges in convergence highlight the complexity of simulating interactions within membrane protein binding sites.