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Herein we report an update to ACPYPE, a Python3 tool that now properly converts AMBER to GROMACS topologies for force fields that utilize nondefault and nonuniform 1–4 electrostatic and nonbonded scaling factors or negative dihedral force constants. Prior to this work, ACPYPE only converted AMBER topologies that used uniform, default 1–4 scaling factors and positive dihedral force constants. We demonstrate that the updated ACPYPE accurately transfers the GLYCAM06 force field from AMBER to GROMACS topology files, which employs non-uniform 1–4 scaling factors as well as negative dihedral force constants. Validation was performed using β-d-GlcNAc through gas-phase analysis of dihedral energy curves and probability density functions. The updated ACPYPE retains all of its original functionality, but now allows the simulation of complex glycomolecular systems in GROMACS using AMBER-originated force fields. ACPYPE is available for download at https://github.com/alanwilter/acpype.
Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia
(2021)
The prognosis of elderly AML patients is still poor due to chemotherapy resistance. The Hedgehog (HH) pathway is important for leukemic transformation because of aberrant activation of GLI transcription factors. MBZ is a well-tolerated anthelmintic that exhibits strong antitumor effects. Herein, we show that MBZ induced strong, dose-dependent anti-leukemic effects on AML cells, including the sensitization of AML cells to chemotherapy with cytarabine. MBZ strongly reduced intracellular protein levels of GLI1/GLI2 transcription factors. Consequently, MBZ reduced the GLI promoter activity as observed in luciferase-based reporter assays in AML cell lines. Further analysis revealed that MBZ mediates its anti-leukemic effects by promoting the proteasomal degradation of GLI transcription factors via inhibition of HSP70/90 chaperone activity. Extensive molecular dynamics simulations were performed on the MBZ-HSP90 complex, showing a stable binding interaction at the ATP binding site. Importantly, two patients with refractory AML were treated with MBZ in an off-label setting and MBZ effectively reduced the GLI signaling activity in a modified plasma inhibitory assay, resulting in a decrease in peripheral blood blast counts in one patient. Our data prove that MBZ is an effective GLI inhibitor that should be evaluated in combination to conventional chemotherapy in the clinical setting.
Human butyrylcholinesterase (BChE) is a glycoprotein capable of bioscavenging toxic compounds such as organophosphorus (OP) nerve agents. For commercial production of BChE, it is practical to synthesize BChE in non-human expression systems, such as plants or animals. However, the glycosylation profile in these systems is significantly different from the human glycosylation profile, which could result in changes in BChE's structure and function. From our investigation, we found that the glycan attached to ASN241 is both structurally and functionally important due to its close proximity to the BChE tetramerization domain and the active site gorge. To investigate the effects of populating glycosylation site ASN241, monomeric human BChE glycoforms were simulated with and without site ASN241 glycosylated. Our simulations indicate that the structure and function of human BChE are significantly affected by the absence of glycan 241.
Structure-activity relationships of thiostrepton derivatives: implications for rational drug design
(2014)
Liquid–liquid equilibria of dipropylene glycol dimethyl ether and water by molecular dynamics
(2011)