Protein Loop Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates

Area of Science:

• Computational biology
• Biophysics
• Molecular dynamics

Background:

• Protein loop reorganization is crucial for biological functions.
• Existing advanced sampling methods like umbrella sampling and metadynamics require predefined collective variables and pathways.
• Previous methods, such as restrain-free energy perturbation-release (R-FEP-R), were limited to protein side chains.

Purpose of the Study:

• To introduce and validate restrain-free energy perturbation-release 2.0 (R-FEP-R 2.0) for estimating protein loop conformational free energy changes.
• To present R-FEP-R 2.0 as a generalization of R-FEP-R, extending its applicability to protein loops.
• To highlight the advantages of R-FEP-R 2.0 over traditional methods by not requiring predetermined collective coordinates.

Main Methods:

• Development of the restrain-free energy perturbation-release 2.0 (R-FEP-R 2.0) alchemical method.
• Application of R-FEP-R 2.0 to calculate the conformational free energy change of a beta-turn flip in ubiquitin.
• Comparative analysis with existing advanced sampling algorithms, noting limitations of umbrella sampling.

Main Results:

• R-FEP-R 2.0 successfully estimated the conformational free energy change of a protein loop (beta-turn flip in ubiquitin).
• The results obtained using R-FEP-R 2.0 showed excellent agreement with benchmark data.
• The study identified common challenges associated with using umbrella sampling for protein conformational free energy calculations.

Conclusions:

• R-FEP-R 2.0 is an effective and versatile method for calculating protein loop conformational free energy changes.
• The method offers a significant advancement over previous techniques by eliminating the need for predefined pathways.
• The findings provide valuable insights into protein dynamics and offer a more robust computational approach for biological research.