The Preferred Conformation of the Tripeptide Ala-Phe-Ala in Water Is an Inverse -Turn: Implications for Protein Folding and Drug Des

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• 作者：Andrea Motta ; Meital Reches ; Lucia Pappalardo ; Giuseppina Andreotti ; and Ehud Gazit
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：November 1, 2005
• 年：2005
• 卷：44
• 期：43
• 页码：14170 - 14178
• 全文大小：138K
• 年卷期：v.44,no.43(November 1, 2005)
• ISSN：1520-4995

文摘

Recent studies have provided evidence that peptides as short as tripeptides do adopt preferredconformations. Here we report that the tripeptide Ala-Phe-Ala (AFA) in aqueous solution preferentiallyforms an inverse G SRC="/images/gifchars/gamma.gif" BORDER=0 >-turn. Circular dichroism (CD) indicated the presence of a predominant turn structure,and Fourier transform infrared (FTIR) bands suggested the presence of a ges/gifchars/gamma.gif" BORDER=0 >-turn forming a bifurcatedH-bond with the solvent molecules. The high-resolution structure was obtained by a combined use ofNMR spectroscopy and calculations. On the basis of 30 unambiguous ROESY-derived distance restraints(including the Hges/gifchars/alpha.gif" BORDER=0>-NH NOE between Ala¹ and Ala³ and a hydrogen bond between the CO group of Ala¹and the NH group of Ala³), calculations clearly demonstrated the presence of an inverse ges/gifchars/gamma.gif" BORDER=0 >-turn centeredon Phe². From NOE data, we estimated a mole fraction for the ges/gifchars/gamma.gif" BORDER=0 >-turn of 0.65. Since for AFA an extendedges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-strand was also reported [Eker, F., Griebenow, K., Cao, X., Nafie, L. A., and Schweitzer-Stenner, R.(2004) Proc. Natl. Acad. Sci. U.S.A. 101, 10054-10059], we investigated the possibility that ges/gifchars/gamma.gif" BORDER=0 >-turn andges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-strand may represent two major conformations. By using a best-fit procedure that calculated experimentalNOEs as weighted averages of the effects originating from both structures, we were able to calculate withgood accuracy the backbone NOEs at 280 K in terms of the two limiting conformers, yielding a molefraction for the ges/gifchars/gamma.gif" BORDER=0 >-turn and ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-strand conformations of 0.60 and 0.40, respectively, in good agreement withthose found by NOE data. The implication of the existence of a preferred conformation by a small structuralelement is discussed in the context of the nucleation of protein folding events and the design of smallpeptide and peptidomimetic drugs.