ABSTRACT
Treatment of calcaneal fractures in patients with diabetes mellitus (DM) is challenging. The purpose of this study was to compare post-operative outcomes after open reduction and internal fixation (ORIF) for calcaneus fracture in patients with complicated DM, uncomplicated DM, and patients without DM. A commercially available de-identified database was queried for all calcaneus fracture diagnoses undergoing ORIF from 2010 to 2021. The patients were separated into three groups for analysis: patients without DM (10,951, 82.6%), uncomplicated DM (1,500, 11.3%) and complicated DM (802, 6.1%). At 1 year, post-operative adverse events were assessed among the three groups. The odds of adverse event(s) for each group were compared between the three groups with and without characteristic matching. In the unmatched cohorts, patients with complicated DM, when compared with patients without DM and patients with uncomplicated DM, had significantly higher rates of all adverse events with exception of DVT. Rates of CNA were significantly higher in patients with complicated DM compared with no DM (OR 107.7 (CI 24.83-467.6) p < 0.0001) and uncomplicated DM (OR 44.26 (CI 3.86-507.93) p = 0.0002). After matching, non-union, AKI, sepsis, surgical site infection, and wound disruption were higher in patients with complicated DM compared with patients without DM. There were no significant differences in the three groups with regard to reoperation, DVT, MI, pneumonia, or below the knee amputation. Patients with DM who underwent ORIF for calcaneus fracture experienced higher rates of post-operative adverse events compared with those patients without DM.
Subject(s)
Calcaneus , Fracture Fixation, Internal , Fractures, Bone , Open Fracture Reduction , Humans , Calcaneus/injuries , Calcaneus/surgery , Fracture Fixation, Internal/adverse effects , Fracture Fixation, Internal/methods , Male , Female , Middle Aged , Fractures, Bone/surgery , Adult , Aged , Treatment Outcome , Postoperative Complications/epidemiology , Databases, Factual , Retrospective Studies , Diabetes Mellitus/epidemiology , Diabetes ComplicationsABSTRACT
Here we show that an NH-π interaction between a highly conserved Asn and a nearby Trp stabilizes the WW domain of the human protein Pin1. The strength of this NH-π interaction depends on the structure of the arene, with NH-π interactions involving Trp or naphthylalanine being substantially more stabilizing than those involving Tyr or Phe. Calculations suggest arene size and polarizability are key structural determinants of NH-π interaction strength. Methylation or PEGylation of the Asn side-chain amide nitrogen each strengthens the associated NH-π interaction, though likely for different reasons. We hypothesize that methylation introduces steric clashes that destabilize conformations in which the NH-π interaction is not possible, whereas PEGylation strengthens the NH-π interaction via localized desolvation of the protein surface.
Subject(s)
Asparagine/chemistry , Hydrogen Bonding/drug effects , NIMA-Interacting Peptidylprolyl Isomerase/chemistry , Polyethylene Glycols/chemistry , Tryptophan/chemistry , WW Domains/drug effects , Amino Acid Sequence , Humans , Methylation , Models, Molecular , Mutation , NIMA-Interacting Peptidylprolyl Isomerase/genetics , Protein Conformation , Thermodynamics , WW Domains/geneticsABSTRACT
Here we show that a solvent-exposed f-position (i.e., residue 14) within a well-characterized trimeric helix bundle can facilitate a stabilizing long-range synergistic interaction involving b-position Glu10 (i.e., i - 4 relative to residue 14) and c-position Lys18 (i.e., i + 4), depending the identity of residue 14. The extent of stabilization associated with the Glu10-Lys18 pair depends primarily on the presence of a side-chain hydrogen-bond donor at residue 14; the nonpolar or hydrophobic character of residue 14 plays a smaller but still significant role. Crystal structures and molecular dynamics simulations indicate that Glu10 and Lys18 do not interact directly with each other but suggest the possibility that the proximity of residue 14 with Lys18 allows Glu10 to interact favorably with nearby Lys7. Subsequent thermodynamic experiments confirm the important role of Lys7 in the large synergistic stabilization associated with the Glu10-Lys18 pair. Our results highlight the exquisite complexity and surprising long-range synergistic interactions among b-, c-, and f-position residues within helix bundles, suggesting new possibilities for engineering hyperstable helix bundles and emphasizing the need to consider carefully the impact of substitutions at these positions for application-specific purposes.
Subject(s)
Peptides/chemistry , Protein Multimerization , Solvents/chemistry , Amino Acid Sequence , Models, Molecular , Protein Conformation, alpha-Helical , Protein Folding , Thermodynamics , Transition TemperatureABSTRACT
Many proteins have one or more surface-exposed patches of nonpolar residues; our observations here suggest that PEGylation near such locations might be a useful strategy for increasing protein conformational stability. Specifically, we show that conjugating a PEG-azide to a propargyloxyphenylalanine via the copper(I)-catalyzed azide-alkyne cycloaddition can increase the conformational stability of the WW domain due to a favorable synergistic effect that depends on the hydrophobicity of a nearby patch of nonpolar surface residues.
