fragHAR: towards ab initio quantum-crystallographic X-ray structure refinement for polypeptides and proteins

Area of Science:

• Crystallography
• Quantum Chemistry
• Structural Biology

Background:

• Accurate protein structure determination is crucial for understanding biological function.
• Quantum crystallographic Hirshfeld atom refinement (HAR) provides highly accurate atomic models but is computationally intensive for large systems.

Purpose of the Study:

• To develop and validate a fragmentation approach for accelerating *ab initio* aspherical structure refinement of proteins using HAR.
• To assess the accuracy and efficiency of the fragmentation method for polypeptide and protein systems.

Main Methods:

• Implementation of a fragmentation strategy within the *TONTO* software to divide proteins into smaller residues and solvent molecules.
• Performing *ab initio* aspherical structure refinement using the fragHAR method on various peptide systems (dipeptides, tripeptides, hexapeptides).
• Comparison of results from fragHAR with conventional HAR on unfragmented systems, with specific attention to hydrogen atom parameters and hydrogen bonds.

Main Results:

• The fragHAR method yields geometric and atomic displacement parameters comparable to standard HAR for small peptides.
• Minor discrepancies were observed for hydrogen atoms involved in hydrogen bonds, which were resolved by adjusting the fragmentation scheme.
• Significant computational speed-ups were achieved for larger systems, enabling highly parallelized HAR.

Conclusions:

• The fragHAR method offers a computationally efficient and accurate approach for *ab initio* aspherical structure refinement of proteins.
• This technique facilitates the application of HAR to larger and more complex biological systems.
• The fragHAR method is now available in the *TONTO* software package.