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Structural Characterization of Histatin 5-Spermidine Conjugates: A Combined Experimental and Theoretical Study.

ABSTRACT: Histatin 5 (Hst5) is a naturally occurring antimicrobial peptide that acts as the first line of defense against oral candidiasis. It has been shown that conjugation of the active Hst5 fragment, Hst54-15, and the polyamine spermidine (Spd) improves the candidacidal effect. Knowledge about the structure of these conjugates is, however, very limited. Thus, the aim of this study was to characterize the structural properties of the Hst54-15-Spd conjugates by performing atomistic molecular dynamics simulations in combination with small-angle X-ray scattering. It was shown that the Hst54-15-Spd conjugates adopt extended and slightly rigid random coil conformations without any secondary structure in aqueous solution. It is hypothesized that the increased fungal killing potential of Hst54-15-Spd, in comparison with the Spd-Hst54-15 conjugate, is due to the more extended conformations of the former, which cause the bonded Spd molecule to be more accessible for recognition by polyamine transporters in the cell.

SUBMITTER: Jephthah S

PROVIDER: S-EPMC5592739 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Structural Characterization of Histatin 5-Spermidine Conjugates: A Combined Experimental and Theoretical Study.

Jephthah Stephanie S Henriques João J Cragnell Carolina C Puri Sumant S Edgerton Mira M Skepö Marie M

Journal of chemical information and modeling 20170606 6

Histatin 5 (Hst5) is a naturally occurring antimicrobial peptide that acts as the first line of defense against oral candidiasis. It has been shown that conjugation of the active Hst5 fragment, Hst5<sub>4-15</sub>, and the polyamine spermidine (Spd) improves the candidacidal effect. Knowledge about the structure of these conjugates is, however, very limited. Thus, the aim of this study was to characterize the structural properties of the Hst5<sub>4-15</sub>-Spd conjugates by performing atomistic ...[more]

PMID: 28586222

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Project description:The transfer of ammonia in carbamoyl phosphate synthetase (CPS) was investigated by molecular dynamics simulations and experimental characterization of mutations within the ammonia tunnel. In CPS, ammonia is derived from the hydrolysis of glutamine and this intermediate must travel approximately 45 A from the site of formation in the small subunit to the site of utilization in the large subunit. In this investigation, the migration of ammonia was analyzed from the exit of the small subunit through the large subunit where it ultimately reacts with the carboxy phosphate intermediate. Potential of mean force calculations along the transfer pathway for ammonia indicate a relatively low free-energy barrier for the translocation of ammonia. The highest barrier of 7.2 kcal/mol is found at a narrow turning gate surrounded by the side chains of Cys-232, Ala-251, and Ala-314 in the large subunit. The environment of the ammonia tunnel from the exit of the small subunit to the turning gate in the tunnel is filled with clusters of water molecules and the ammonia is able to travel through this area easily. After ammonia passes through the turning gate, it enters a hydrophobic passage. A hydrogen bond then forms between the ammonia and Thr-249, which facilitates the delivery to a more hydrophilic environment near the active site for the reaction with the carboxy phosphate intermediate. The transport process from the turning gate to the end of the tunnel is favored by an overall downhill free-energy potential and no free-energy barrier higher than 3 kcal/mol. A conformational change of the turning gate, caused by formation of the carboxy phosphate intermediate, is consistent with a mechanism in which the reaction between ATP and bicarbonate triggers the transport of ammonia and consequently accelerates the rate of glutamine hydrolysis in the small subunit. A blockage in the turning gate passageway was introduced by the triple mutant C232V/A251V/A314V. This mutant is unable to synthesize carbamoyl phosphate using glutamine as a nitrogen source.

Dataset Information

Structural Characterization of Histatin 5-Spermidine Conjugates: A Combined Experimental and Theoretical Study.

Publications

Structural Characterization of Histatin 5-Spermidine Conjugates: A Combined Experimental and Theoretical Study.

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