Electrostatic Potential on Human Leukocyte Antigen: Implications for Putative Mechanism of Chronic Beryllium Disease

Snyder, James A.; Weston, Ainsley; Tinkle, Sally S.; Demchuk, Eugene

doi:10.1289/txg.6327

Cited by 4 publications

(8 citation statements)

References 12 publications

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“…A recent study demonstrates that individuals with BeS or CBD are significantly more likely to be homozygous for E69 than heterozygous 1 (odds ratio (OR), 3.1; 95% confidence interval (CI), 1.5-6.1), and that individuals with CBD are significantly more likely to have inherited an HLA-DPb1 Ã E69 allele than individuals with BeS (OR, 2.3; 95% CI, 1.1-4.8; McCanlies et al 2004). Based on these data, analyses of literature reports (Saltini et al 2001;Rossman et al 2002;Maier et al 2003;McCanlies et al 2003) and information from molecular modelling ( Fontenot et al 2000), we framed three formal hypotheses, details of which are elaborated elsewhere (Snyder et al 2003;Weston et al 2005a). We considered the two most abundant classes of HLA-DPb1 Ã E69 alleles (frequencies of 0.28 and 0.56 of HLA-DPb1 Ã E69 alleles, respectively), defined by the total negative charges of K9 or K7 on the titratable groups from the HVRs on the HLA molecules for which the alleles code (Rossman et al 2002;Robinson et al 2003;McCanlies et al 2004;Weston et al 2005a;Marsh 2007).…”

Section: Resultsmentioning

confidence: 99%

“…rcsb.org/pdb). We modelled the extracellular part of HLA-DP by homology to a known HLA species (Snyder et al 2003). All molecular dynamics (MD) simulations were performed using CHARMM v. 30 with the CHARMM22 force field (Brooks et al 1983;MacKerell et al 1998).…”

Section: Molecular Dynamics and Free Energy Perturbationmentioning

confidence: 99%

“…Early molecular genetics reports, although constrained by small populations and lack of X-ray data, alluded to the pivotal structural role of HVRs in CBD (Richeldi et al 1993;Fontenot et al 2000). Recently, a new structural model for HLA-DP has been proposed (Snyder et al 2003). This model, developed with full atomistic details, has facilitated formulation of new epidemiologic hypotheses (Weston et al 2005a) that were tested in the present study using blood samples from a large cohort of 854 beryllium-exposed workers.…”

Section: Introductionmentioning

confidence: 95%

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Impact of negatively charged patches on the surface of MHC class II antigen-presenting proteins on risk of chronic beryllium disease

Snyder

Demchuk

McCanlies

et al. 2007

J. R. Soc. Interface.

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Chronic beryllium disease (CBD) is a granulomatous lung disease that occurs primarily in workers who are exposed to beryllium dust or fumes. Although exposure to beryllium is a necessary factor in the pathobiology of CBD, alleles that code for a glutamic acid residue at the 69th position of the HLA-DPb1 gene have previously been found to be associated with CBD. To date, 43 HLA-DPb1 alleles that code for glutamic acid 69 (E69) have been described. Whether all of these E69 coding alleles convey equal risk of CBD is unknown. The present study demonstrates that, on the one hand, E69 alleloforms of major histocompatibility complex class II antigen-presenting proteins with the greatest negative surface charge convey the highest risk of CBD, and on the other hand, irrespective of allele, they convey equal risk of beryllium sensitization (BeS). In addition, the data suggest that the same alleles that cause the greatest risk of CBD are also important for the progression from BeS to CBD. Alleles convey the highest risk code for E26 in a constant region and for E69, aspartic acid 55 (D55), E56, D84 and E85 in hypervariable regions of the HLA-DPb1 chain. Together with the calculated high binding affinities for beryllium, these results suggest that an adverse immune response, leading to CBD, is triggered by chemically specific metal-protein interactions.

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Section: Resultsmentioning

confidence: 99%

Section: Molecular Dynamics and Free Energy Perturbationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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Impact of negatively charged patches on the surface of MHC class II antigen-presenting proteins on risk of chronic beryllium disease

Snyder

Demchuk

McCanlies

et al. 2007

J. R. Soc. Interface.

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“…There have been some efforts on inferring binding sites of beryllium ions in proteins on the basis of ab initio studies of Be 2+ binding sites in small inorganic molecule mimics 4 and the electrostatic potentials of proteins. 5 We believe that classical molecular dynamics (MD) simulations are essential for providing an atomistic description of Be 2+ interactions and for identifying potential binding sites in relevant biological systems, such as human lung surfactant proteins and major histocompatibility complex II proteins associated with CBD. Therefore, it is imperative that we develop accurate, but simple, potential parameters for Be 2+ that can be used with large-scale classical simulations of the biomolecules for elucidation of binding sites.…”

Section: Introductionmentioning

confidence: 99%

Perturbation of Local Solvent Structure by a Small Dication: A Theoretical Study on Structural, Vibrational, and Reactive Properties of Beryllium Ion in Water

et al. 2008

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A molecular based understanding of beryllium chemistry in the context of biomolecules is necessary for gaining progress in prevention and treatment of chronic beryllium disease. One aspect that has hindered the theoretical progress has been the lack of a simple classical two-body potential for the aqueous beryllium ion (Be2+) to be used with biomolecular simulations. We provide new parameters for Be2+ that capture the structural and reactive properties of this small dication. Using classical molecular dynamics simulations, we show that these parameters reproduce the correct radial distribution function and coordination numbers for this cation in explicit aqueous solution when compared to published diffraction and NMR measurements. The geometrical parameters obtained using classical simulations are also in agreement with ab initio calculations. We successfully predict the vibrational modes of the tetra aqua Be2+ dication from ab initio calculations on solvated structures obtained from the simulations. The calculated vibrational modes show better agreement with experiments compared to any published work. This new potential also produces a well-established hydrogen bonding between the first and second solvation shells. More importantly, when the molecular dynamics (MD) and ab initio results are interpreted in concert, the dynamics and nature of interactions between the first and second shells capture the pivotal role they play on the reactivity of aqua-Be complexes.

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“…Support for this idea comes from a study by Keizer et al (2005) showing that at physiologic pH, Be forms stable ring clusters with oxygen. The HLA-DP peptide binding pocket contains six carboxylate groups and Be may therefore form stable complexes bound via one or more of these carboxylates (Scott et al 2003; Snyder et al 2003; Keizer et al 2005). …”

Section: The Complete Chemical Composition Of Be-antigen Was Unknownmentioning

confidence: 99%

Chronic beryllium disease: an updated model interaction between innate and acquired immunity

Sawyer

Maier

2010

Biometals

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During the last decade, there have been concerted efforts to reduce beryllium (Be) exposure in the workplace and thereby reduce potential cases of this occupational lung disorder. Despite these efforts, it is estimated that there are at least one million Be-exposed individuals in the U.S. who are potentially at risk for developing chronic beryllium disease (CBD). Previously, we reviewed the current CBD literature and proposed that CBD represents a model interaction between innate and acquired immunity (Sawyer et al., Int Immunopharmacol 2:249–261, 2002). We closed this review with a section on “future directions” that identified key gaps in our understanding of the pathogenesis of CBD. In the intervening period, progress has been made to fill in some of these gaps, and the current review will provide an update on that progress. Based on recent findings, we provide a new hypothesis to explain how Be drives sustained chronic inflammation and granuloma formation in CBD leading to progressive compromised lung function in CBD patients. This paradigm has direct implications for our understanding of the development of an immune response to Be, but is also likely applicable to other immune-mediated lung diseases of known and unknown etiology.

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Electrostatic Potential on Human Leukocyte Antigen: Implications for Putative Mechanism of Chronic Beryllium Disease

Cited by 4 publications

References 12 publications

Impact of negatively charged patches on the surface of MHC class II antigen-presenting proteins on risk of chronic beryllium disease

Impact of negatively charged patches on the surface of MHC class II antigen-presenting proteins on risk of chronic beryllium disease

Perturbation of Local Solvent Structure by a Small Dication: A Theoretical Study on Structural, Vibrational, and Reactive Properties of Beryllium Ion in Water

Chronic beryllium disease: an updated model interaction between innate and acquired immunity

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