Identification and insertion of 3-carbon bridges in protein disulfide bonds: a computational approach

Zloh, Mire; Shaunak, Sunil; Balan, Sibu; Brocchini, Steve

doi:10.1038/nprot.2007.119

Cited by 24 publications

(25 citation statements)

References 28 publications

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“…A 100 ps equilibration simulation was preceded by 2500 steps of minimization. A 2 ns production run was performed as previously described[22]. A sample structure was recorded for every 10 ps of the simulation for trajectory analysis.…”

Section: Methodsmentioning

confidence: 99%

Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex

et al. 2011

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The cell surface interaction between bacterial lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) and MD-2 is central to bacterial sepsis syndromes and wound healing. We have shown that a generation (G) 3.5 polyamidoamine (PAMAM) dendrimer that was partially glycosylated with glucosamine inhibits TLR4-MD-2-LPS induced inflammation in a rabbit model of tissue scaring. However, it was a mixture of closely related chemical species because of the polydispersity of the starting PAMAM dendrimer. Generation 2 triazine dendrimers with single chemical entity material status are available at low cost and at the kilogram scale. PAMAM dendrimer can be synthetically grafted onto this triazine core dendrimer to make new triazine-PAMAM hybrid dendrimers. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule that could be synthesized and biologically evaluated. We describe our computer aided molecular studies of several dendrimer based constructs and the key design principles identified. Our approach should be more broadly applicable to the biologically focused, rational and accelerated design of molecules for other TLR receptors. They could be useful for treating infectious, inflammatory and malignant diseases.

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Section: Methodsmentioning

confidence: 99%

Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex

et al. 2011

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“…UV-vis analysis of isolated (3b)-sCT showed a maximum at λ = 471 nm, and upon lowering gradually the pH to 5.0, a disappearance of this was observed, with the formation of a band at λ = 372 nm (Figure 3). For comparison purposes, the diazonium salt of (3b) was conjugated with water-soluble model histidine (8) and tyrosine (9) mimics. UV-vis spectra of the isolated conjugates (3b)- (8) prepared from a His mimic showed very little, if any, dependence on the pH.…”

Section: Characterization Of Sct-polymer Conjugates: Attachment Sitementioning

confidence: 99%

“…Figure 4. UV-Vis spectra of (3b)-sCT and purified conjugates of (3b) with histidine (8), and tyrosine (9) mimics, at various pH.…”

Section: Characterization Of Sct-polymer Conjugates: Attachment Sitementioning

confidence: 99%

Direct Peptide Bioconjugation/PEGylation at Tyrosine with Linear and Branched Polymeric Diazonium Salts

et al. 2012

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Direct polymer conjugation at peptide tyrosine residues is described. In this study Tyr residues of both leucine enkephalin and salmon calcitonin (sCT) were targeted using appropriate diazonium salt-terminated linear monomethoxy poly(ethylene glycol)s (mPEGs) and poly(mPEG) methacrylate prepared by atom transfer radical polymerization. Judicious choice of the reaction conditionspH, stoichiometry, and chemical structure of diazonium saltled to a high degree of site-specificity in the conjugation reaction, even in the presence of competitive peptide amino acid targets such as histidine, lysines, and N-terminal amine. In vitro studies showed that conjugation of mPEG2000 to sCT did not affect the peptide’s ability to increase intracellular cAMP induced in T47D human breast cancer cells bearing sCT receptors. Preliminary in vivo investigation showed preserved ability to reduce [Ca2+] plasma levels by mPEG2000-sCT conjugate in rat animal models.

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“…One advantage of our software is that it calculates an energy value for each candidate disulfide, thus providing a means to rank potential disulfide bonds. The original Disulfide by Design application has been downloaded over 1000 times and used in a wide variety of applications [17-21]. While it has proven very useful in numerous disulfide engineering projects, our original software has a number of limitations.…”

Section: Introductionmentioning

confidence: 99%

Disulfide by Design 2.0: a web-based tool for disulfide engineering in proteins

2013

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BackgroundDisulfide engineering is an important biotechnological tool that has advanced a wide range of research. The introduction of novel disulfide bonds into proteins has been used extensively to improve protein stability, modify functional characteristics, and to assist in the study of protein dynamics. Successful use of this technology is greatly enhanced by software that can predict pairs of residues that will likely form a disulfide bond if mutated to cysteines.ResultsWe had previously developed and distributed software for this purpose: Disulfide by Design (DbD). The original DbD program has been widely used; however, it has a number of limitations including a Windows platform dependency. Here, we introduce Disulfide by Design 2.0 (DbD2), a web-based, platform-independent application that significantly extends functionality, visualization, and analysis capabilities beyond the original program. Among the enhancements to the software is the ability to analyze the B-factor of protein regions involved in predicted disulfide bonds. Importantly, this feature facilitates the identification of potential disulfides that are not only likely to form but are also expected to provide improved thermal stability to the protein.ConclusionsDbD2 provides platform-independent access and significantly extends the original functionality of DbD. A web server hosting DbD2 is provided at http://cptweb.cpt.wayne.edu/DbD2/.

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Identification and insertion of 3-carbon bridges in protein disulfide bonds: a computational approach

Cited by 24 publications

References 28 publications

Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex

Computational design principles for bioactive dendrimer based constructs as antagonists of the TLR4-MD-2-LPS complex

Direct Peptide Bioconjugation/PEGylation at Tyrosine with Linear and Branched Polymeric Diazonium Salts

Disulfide by Design 2.0: a web-based tool for disulfide engineering in proteins

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