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Optimal allosteric stabilization sites using contact stabilization analysis.

ABSTRACT: Proteins can be destabilized by a number of environmental factors such as temperature, pH, and mutation. The ability to subsequently restore function under these conditions by adding small molecule stabilizers, or by introducing disulfide bonds, would be a very powerful tool, but the physical principles that drive this stabilization are not well understood. The first problem lies is in choosing an appropriate binding site or disulfide bond location to best confer stability to the active site and restore function. Here, we present a general framework for predicting which allosteric binding sites correlate with stability in the active site. Using the Karanicolas-Brooks G?-like model, we examine the dynamics of the enzyme ?-glucuronidase using an Umbrella Sampling method to thoroughly sample the conformational landscape. Each intramolecular contact is assigned a score termed a "stabilization factor" that measures its correlation with structural changes in the active site. We have carried out this analysis for three different scaling strengths for the intramolecular contacts, and we examine how the calculated stabilization factors depend on the ensemble of destabilized conformations. We further examine a locally destabilized mutant of ?-glucuronidase that has been characterized experimentally, and show that this brings about local changes in the stabilization factors. We find that the proximity to the active site is not sufficient to determine which contacts can confer active site stability. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Dickson A

PROVIDER: S-EPMC5403592 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Optimal allosteric stabilization sites using contact stabilization analysis.

Dickson Alex A Bailey Christopher T CT Karanicolas John J

Journal of computational chemistry 20161024 15

Proteins can be destabilized by a number of environmental factors such as temperature, pH, and mutation. The ability to subsequently restore function under these conditions by adding small molecule stabilizers, or by introducing disulfide bonds, would be a very powerful tool, but the physical principles that drive this stabilization are not well understood. The first problem lies is in choosing an appropriate binding site or disulfide bond location to best confer stability to the active site and ...[more]

PMID: 27774625

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Project description:Fever screening is an effective method to detect infectors associated with different variants of coronavirus disease 2019 (COVID-19) based on the fact that most infectors with COVID-19 have fever symptoms. Non-contact infrared thermometers (NCITs) are widely used in fever screening. Nevertheless, authoritative data is lacking in defining "fever" at different body surface sites when using NCITs. The purpose of this study was to determine the optimal diagnostic threshold for fever screening using NICTs at different body surface sites, to improve the accuracy of fever screening and provide theoretical reference for healthcare policy. Participants (n = 1860) who were outpatients or emergency patients at Chengdu Women's and Children's Central Hospital were recruited for this prospective investigation from March 1 to June 30, 2021. NCITs and mercury axillary thermometers were used to measure neck, temple, forehead and wrist temperatures of all participants. Receiver operating characteristic curves were used to reflect the accuracy of NCITs. Linear correlation analysis was used to show the effect of age on body temperature. Multilinear regression analysis was used to explore the association between non-febrile participant's covariates and neck temperature. The mean age of participants was 3.45 ± 2.85 years for children and 28.56 ± 7.25 years for adults. In addition 1,304 (70.1%) participants were children (≤12), and 683 (36.7%) were male. The neck temperature exhibited the highest accuracy among the four sites. Further the optimal fever diagnostic thresholds of NCITs at the four body surface measurement sites were neck (36.75 °C, sensitivity: 0.993, specificity: 0.858); temple (36.55 °C, sensitivity: 0.974, specificity: 0.874); forehead (36.45 °C, sensitivity: 0.961, specificity: 0.813); and wrist (36.15 °C, sensitivity: 0.951, specificity: 0.434). Based on the findings of our study, we recommend 36.15, 36.45, 36.55, and 36.75 °C as the diagnostic thresholds of fever at the wrist, forehead, temple and neck, respectively. Among the four surface sites, neck temperature exhibited the highest accuracy.

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Optimal allosteric stabilization sites using contact stabilization analysis.

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Optimal allosteric stabilization sites using contact stabilization analysis.

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