2015 · Oda et al. — Prediction of binding modes between protein L-isoaspartyl (D-aspartyl) O-methyltransferase and peptide substrates including isomerized aspartic acid residues using in silico analytic methods for the substrate screening.
Super-Abstract
Computational docking and molecular dynamics simulation successfully predicted how the DNA-repair enzyme PIMT recognises isomerised aspartic acid variants in peptide substrates — distinguishing true substrates from non-substrates purely in silico. The method could accelerate substrate screening in aging and protein-damage research. This study has no connection to molecular hydrogen (H₂) biology.
Commentary
Protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PIMT) is a repair enzyme that corrects spontaneously isomerised aspartic acid residues in proteins — a damage process that accumulates with aging. Understanding which peptide sequences PIMT recognises is important for aging biology and potential therapeutics. This study uses computational protein-ligand docking and MD simulation to predict binding modes for four Asp isomers (L-α, L-β, D-α, D-β-Asp). The simulations correctly identify L-β-Asp and D-α-Asp as substrates (carboxyl group recognition in similar orientations) while L-α-Asp and D-β-Asp non-substrates showed distinct binding geometries and more rigid conformations driven by intramolecular hydrogen bonds. The paper contributes to structural enzymology and aging research but has no relevance to molecular hydrogen (H₂) therapy. The term „hydrogen“ refers exclusively to conventional intramolecular hydrogen bonds within peptide substrates.
Key quotes
- „carboxyl groups of both l-β-Asp and D-α-Asp were recognized in similar modes by PIMT and that the C-terminal regions of substrate peptides were located in similar positions on PIMT for both the l-β-Asp and D-α-Asp peptides.“ — substrate recognition result: both true substrates bind PIMT in comparable orientations
- „In the nonsubstrate peptides, not inter- but intra-molecular hydrogen bonds were observed, and the conformations of peptides were more rigid than those of substrates.“ — non-substrate result: intramolecular hydrogen bonds lock non-substrates in unproductive conformations
- „the in silico analytical methods were able to distinguish substrates from nonsubstrates and the computational methods are expected to complement experimental analytical methods.“ — validation conclusion: the computational approach is reliable for substrate screening
Our assessment
A well-executed computational study in structural enzymology. The finding that in-silico methods can distinguish PIMT substrates from non-substrates has practical value for high-throughput substrate screening in aging-related protein-damage research. The study has no relevance to molecular hydrogen (H₂) medicine; it deals with hydrogen bonds as a fundamental biochemical concept. Its presence in H₂ databases reflects keyword matching artefact, not scientific relevance to H₂ therapy.
Study design
- Type: in-silico computational study · Model: protein-ligand docking + MD simulation of PIMT with four Asp isomers (L-α, L-β, D-α, D-β-Asp) · H₂ relevance: none
- Method: computational docking + molecular dynamics simulation · Result: L-β-Asp and D-α-Asp substrates show similar binding geometry; non-substrates L-α and D-β-Asp show intra-molecular H-bonds and rigid conformations inconsistent with productive binding
Abstract
Because the aspartic acid (Asp) residues in proteins are occasionally isomerized in the human body, not only l-α-Asp but also l-β-Asp, D-α-Asp and D-β-Asp are found in human proteins. In these isomerized aspartic acids, the proportion of D-β-Asp is the largest and the proportions of l-β-Asp and D-α-Asp found in human proteins are comparatively small. To explain the proportions of aspartic acid isomers, the possibility of an enzyme able to repair l-β-Asp and D-α-Asp is frequently considered. The protein L-isoaspartyl (D-aspartyl) O-methyltransferase (PIMT) is considered one of the possible repair enzymes for l-β-Asp and D-α-Asp. Human PIMT is an enzyme that recognizes both l-β-Asp and D-α-Asp, and catalyzes the methylation of their side chains. In this study, the binding modes between PIMT and peptide substrates containing l-β-Asp or D-α-Asp residues were investigated using computational protein-ligand docking and molecular dynamics simulations. The results indicate that carboxyl groups of both l-β-Asp and D-α-Asp were recognized in similar modes by PIMT and that the C-terminal regions of substrate peptides were located in similar positions on PIMT for both the l-β-Asp and D-α-Asp peptides. In contrast, for peptides containing l-α-Asp or D-β-Asp residues, which are not substrates of PIMT, the computationally constructed binding modes between PIMT and peptides greatly differed from those between PIMT and substrates. In the nonsubstrate peptides, not inter- but intra-molecular hydrogen bonds were observed, and the conformations of peptides were more rigid than those of substrates. Thus, the in silico analytical methods were able to distinguish substrates from nonsubstrates and the computational methods are expected to complement experimental analytical methods.
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