Protein sequence optimization with a pairwise decomposable penalty for buried unsatisfied hydrogen bonds

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Polar groups in proteins typically form hydrogen bonds with water in aqueous solutions.
• Burial of polar groups within a protein's interior is energetically unfavorable without compensatory internal hydrogen bond formation.
• Unsatisfied polar groups, which lack hydrogen bond partners, are rare in proteins due to this energetic penalty.

Purpose of the Study:

• To develop a computationally efficient method for penalizing buried unsatisfied polar groups during protein design.
• To integrate this penalty into a pairwise-decomposable energy term for sidechain rotamer packing.
• To improve the accuracy of protein structure prediction and design by accounting for hydrogen bonding energetics.

Main Methods:

• Developed a method to assign pairwise-decomposable energy terms to sidechain rotamers.
• Implemented a penalty based on the number of unsatisfied polar groups, calculable as a quadratic function.
• Integrated this energy term into the Rosetta sidechain packing algorithm.

Main Results:

• The new method successfully penalizes buried unsatisfied polar groups after combinatorial sidechain packing.
• Inclusion of the penalty term significantly reduced the occurrence of buried unsatisfied polar groups in calculations.
• The penalty term is computationally efficient and rapidly calculable.

Conclusions:

• The described method provides an effective way to model the energetic cost of unsatisfied hydrogen bonds in protein interiors.
• This approach enhances protein design by minimizing unfavorable polar group interactions.
• The findings have implications for improving computational protein modeling and design strategies.