Exploring human porphobilinogen synthase metalloprotein by quantum biochemistry and evolutionary methods

Area of Science:

• Biochemistry and Molecular Biology
• Computational Chemistry
• Bioinformatics

Background:

• Porphobilinogen synthase (PBGS) is essential in heme biosynthesis and conserves its zinc-binding mechanism across species.
• The precise molecular interactions of zinc within the PBGS active site remain incompletely understood.
• Density functional theory (DFT) offers a balance of accuracy and computational feasibility for studying metalloproteins.

Purpose of the Study:

• To elucidate the molecular interactions of zinc with human PBGS using DFT-based models.
• To identify conserved residues forming the zinc-binding site through phylogenetic and clustering analyses.
• To benchmark the performance of different DFT models for metalloprotein studies.

Main Methods:

• Employed DFT calculations with the molecular fractionation with conjugate caps (MFCC) scheme to model zinc-PBGS interactions.
• Utilized phylogenetic and unsupervised clustering analyses on protein sequences to identify conserved residues.
• Performed benchmark analyses of computational models to assess accuracy and efficiency.

Main Results:

• Identified key amino acids (CYS0122, CYS0124, CYS0132, ASP0169, SER0168, ARG0221, HIS0131, ASP0120, GLY0133, VAL0121, ARG0209, ARG0174) involved in zinc binding.
• Highlighted ASP0120, GLY0133, HIS0131, SER0168, and ARG0209 as consistently important residues across clustering analyses.
• Observed that triple cysteine residues (CYS0122, CYS0124, CYS0132) exhibit strong zinc attraction but are absent in certain taxa like Viridiplantae.

Conclusions:

• The study provides a detailed molecular understanding of zinc coordination in human PBGS.
• Conserved residues identified are critical for enzyme function and can inform future drug design.
• DFT models are effective for studying metalloproteins, with basis set choice impacting processing time more than the functional.