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Hydrophobic core mutations in CI2 globally perturb fast side-chain dynamics similarly without regard to position.

ABSTRACT: Protein dynamics is currently an area of intense research because of its importance as complementary information to the huge quantity of available data relating protein structure and function. Because it is usually the influence of dynamics on function that is studied, the physical determinants of the distribution of flexibility in proteins have not been explored as thoroughly. In the present NMR study, an expanded suite of five (2)H relaxation experiments was used to characterize the picosecond-to-nanosecond side-chain dynamics of chymotrypsin inhibitor 2 (CI2) and five hydrophobic core mutants, some of which are members of the folding nucleus. Because CI2 is a homologue of the serine protease inhibitor eglin c, which has already been extensively characterized in terms of its dynamics, it was possible to compare not only side-chain dynamics but also the responses of these dynamics to analogous mutations. Remarkably, each of the five core mutations in CI2 led to similar and reproducible increases in side-chain flexibility throughout the entire structure. Although the expanded suite of (2)H relaxation experiments does not affect model selection for the vast majority of residues, it did enable the detection of increasing levels of nanosecond-scale motions in CI2's reactive site binding loop as the L68 side chain was progressively shortened by mutation. Collectively, we observed that the CI2 mutants are more dynamically similar to each other than to the more rigid wild-type CI2, from which we propose that wild-type CI2 has been optimized to a specific level of rigidity which may aid in its function as a serine protease inhibitor. We also observed that the pattern of side-chain dynamics of CI2 is quantitatively similar to eglin c, but that this similarity is lost upon mutating both proteins at an equivalent position. Finally, (15)N relaxation was used to characterize the backbone dynamics of wild-type and mutant CI2. Interestingly, mutation at folding nucleus positions led to widespread increases in backbone flexibility, whereas non-folding-nucleus positions led to increases in flexibility in the C-terminal half of the protein only.

SUBMITTER: Whitley MJ

PROVIDER: S-EPMC2661030 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Hydrophobic core mutations in CI2 globally perturb fast side-chain dynamics similarly without regard to position.

Whitley Matthew J MJ Zhang Jun J Lee Andrew L AL

Biochemistry 20080726 33

Protein dynamics is currently an area of intense research because of its importance as complementary information to the huge quantity of available data relating protein structure and function. Because it is usually the influence of dynamics on function that is studied, the physical determinants of the distribution of flexibility in proteins have not been explored as thoroughly. In the present NMR study, an expanded suite of five (2)H relaxation experiments was used to characterize the picosecond ...[more]

PMID: 18656953

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Project description:There is an increasing trend toward broiler production systems with higher welfare requirements. Breed and stocking density are considered key factors for broiler welfare that are often specified as criteria for such higher welfare systems. However, it remains unknown how slower-growing broilers respond to a reduction in stocking density with regard to their welfare and performance, and whether this response differs from fast-growing broilers. Therefore, we compared fast- (F) and slower-growing broilers (S) housed at 4 different stocking densities (24, 30, 36, and 42 kg/m2, based on slaughter weight) and measured their welfare scores (i.e., gait, footpad dermatitis, hock burn, skin lesions and cleanliness), litter quality and performance. The experiment had a 2 × 4 factorial design with 4 replicates (pens) per treatment (32 pens in total). Thinning (15%) was done in a 50/50 male/female ratio at 38 (F) and 44 (S) d of age (estimated body weight of 2.2 kg). We hypothesized that breeds would respond differently to a reduction in stocking density. Contrary to our hypothesis, only one interaction between breed and stocking density was found on footpad dermatitis, indicating that fast- and slower-growing broilers generally showed similar responses to a reduction in stocking density. F broilers showed a steeper decline in the prevalence of footpad dermatitis with reducing stocking density compared to S broilers. Broilers housed at lower stocking densities (24 and/or 30 kg/m2) showed improved welfare measures, litter quality and performance compared to those housed at higher stocking densities (36 and/or 42 kg/m2). S broilers had better welfare scores (gait, footpad dermatitis and skin lesions), litter quality and lower performance compared to F broilers. In conclusion, reducing stocking density improved welfare of both F and S broilers, but more for F broilers in case of footpad dermatitis, and using S broilers improved welfare compared to F broilers. Reducing stocking density and using slower-growing broilers benefits broiler welfare, where combining both would further improve broiler welfare.

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Hydrophobic core mutations in CI2 globally perturb fast side-chain dynamics similarly without regard to position.

Publications

Hydrophobic core mutations in CI2 globally perturb fast side-chain dynamics similarly without regard to position.

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