Separated topologies--a method for relative binding free energy calculations using orientational restraints.

Area of Science:

• Computational chemistry
• Molecular modeling
• Biophysics

Background:

• Alchemical free energy calculations are crucial for determining ligand binding affinities.
• Orientational restraints improve calculation efficiency but are underutilized in relative binding studies.
• Existing methods often require ligands to maintain a shared orientation, leading to convergence issues.

Purpose of the Study:

• To introduce and validate a new "separated topologies" method for relative binding free energy calculations.
• To demonstrate the advantages of using orientational restraints in relative binding free energy computations.
• To enable the calculation of relative free energies for multiple ligand orientations.

Main Methods:

• Developed a "separated topologies" approach for alchemical free energy calculations.
• Applied orientational restraints within the separated topologies framework.
• Calculated relative binding free energies for two compounds binding to Cytochrome C Peroxidase.

Main Results:

• The separated topologies method avoids a slow reorientation step common in standard calculations.
• This new method allows distinct initial and final ligand orientations.
• Successfully calculated relative binding free energies for compounds binding to Cytochrome C Peroxidase.

Conclusions:

• The separated topologies method offers an efficient alternative for relative binding free energy calculations.
• This approach improves upon existing methods by allowing distinct ligand orientations.
• The method is applicable to determining relative free energies for multiple ligand orientations.