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Side-chain to backbone interactions dictate the conformational preferences of a cyclopentane arginine analogue.

ABSTRACT: The intrinsic conformational preferences of the nonproteinogenic amino acids constructed by incorporating the arginine side chain in the beta position of 1-aminocyclopentane-1-carboxylic acid (either in a cis or a trans orientation relative to the amino group) have been investigated by using computational methods. These compounds may be considered as constrained analogues of arginine (denoted as c(5)Arg) in which the orientation of the side chain is fixed by the cyclopentane moiety. Specifically, the N-acetyl-N'-methylamide derivatives of cis- and trans-c(5)Arg have been examined in the gas phase and in solution by using B3LYP/6-311+G(d,p) calculations and Molecular Dynamics simulations. Results indicate that the conformational space available to these compounds is highly restricted, their conformational preferences being dictated by the ability of the guanidinium group in the side chain to establish hydrogen bond interactions with the backbone. A comparison with the behavior previously described for the analogous phenylalanine derivatives is presented.

SUBMITTER: Revilla-Lopez G

PROVIDER: S-EPMC2682113 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Side-chain to backbone interactions dictate the conformational preferences of a cyclopentane arginine analogue.

Revilla-López Guillem G Torras Juan J Jiménez Ana I AI Cativiela Carlos C Nussinov Ruth R Alemán Carlos C

The Journal of organic chemistry 20090301 6

The intrinsic conformational preferences of the nonproteinogenic amino acids constructed by incorporating the arginine side chain in the beta position of 1-aminocyclopentane-1-carboxylic acid (either in a cis or a trans orientation relative to the amino group) have been investigated by using computational methods. These compounds may be considered as constrained analogues of arginine (denoted as c(5)Arg) in which the orientation of the side chain is fixed by the cyclopentane moiety. Specifically ...[more]

PMID: 19236034

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Project description:Coupled motions have been demonstrated to be functionally important in a number of enzymes. Noncovalent side-chain interactions play essential roles in coordinating the motions across different structural elements in a protein. However, most of the dynamic studies of proteins are focused on backbone amides or methyl groups in the side chains and little is known about the polar and charged side chains. We have previously characterized the conformational dynamics of deubiquitinase A (DUBA), an isopeptidase, on the microsecond-to-millisecond (μs-ms) time scales with the amide 1H Carr-Purcell-Meiboom-Gill (CPMG) experiment. We detected a global conformational exchange process on a time scale of approximately 200 μs, which involves most of the structural elements in DUBA, including the active site and the substrate binding interface. Here, we extend our previous study on backbone amides to the arginine side-chain Nε-Hε groups using a modified 1H CPMG pulse sequence that can efficiently detect both backbone amide and arginine side-chain Nε-Hε signals in a single experiment. We found that the side chains of three arginines display motions on the same time scale as the backbone amides. Mutations of two of the three arginines to alanines result in a decrease in enzyme activity. One of these two arginines is located in a loop involved in substrate binding. This loop is not visible in the backbone amide-detected experiments due to excess line broadening induced by motions on the μs-ms time scales. These results clearly demonstrate that the motions of some arginine side chains are coupled to the global conformational exchange process and provide an additional probe for motions in a functionally important loop that did not yield visible backbone amide signals, suggesting the value of side-chain experiments on DUBA. The modified 1H CPMG pulse sequence allows the simultaneous characterization of backbone and arginine side-chain dynamics without any increase in data acquisition time and can be applied to the dynamic studies of any protein that displays measurable amide 1H relaxation dispersion.

Dataset Information

Side-chain to backbone interactions dictate the conformational preferences of a cyclopentane arginine analogue.

Publications

Side-chain to backbone interactions dictate the conformational preferences of a cyclopentane arginine analogue.

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