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Polyol and sugar osmolytes can shorten protein hydrogen bonds to modulate function.

ABSTRACT: Polyol and sugar osmolytes are commonly used in therapeutic protein formulations. How they may affect protein structure and function is an important question. In this work, through NMR measurements, we show that glycerol and sorbitol (polyols), as well as glucose (sugar), can shorten protein backbone hydrogen bonds. The hydrogen bond shortening is also captured by molecular dynamics simulations, which suggest a hydrogen bond competition mechanism. Specifically, osmolytes weaken hydrogen bonds between the protein and solvent to strengthen those within the protein. Although the hydrogen bond change is small, with the average experimental cross hydrogen bond ^3hJ_NC' coupling of two proteins GB3 and TTHA increased by ~ 0.01?Hz by the three osmolytes (160?g/L), its effect on protein function should not be overlooked. This is exemplified by the PDZ3-peptide binding where several intermolecular hydrogen bonds are formed and osmolytes shift the equilibrium towards the bound state.

SUBMITTER: Li J

PROVIDER: S-EPMC7511342 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Polyol and sugar osmolytes can shorten protein hydrogen bonds to modulate function.

Li Jingwen J Chen Jingfei J An Liaoyuan L Yuan Xiaoxiang X Yao Lishan L

Communications biology 20200923 1

Polyol and sugar osmolytes are commonly used in therapeutic protein formulations. How they may affect protein structure and function is an important question. In this work, through NMR measurements, we show that glycerol and sorbitol (polyols), as well as glucose (sugar), can shorten protein backbone hydrogen bonds. The hydrogen bond shortening is also captured by molecular dynamics simulations, which suggest a hydrogen bond competition mechanism. Specifically, osmolytes weaken hydrogen bonds be ...[more]

PMID: 32968183

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Project description:The growing number of high-resolution crystal structures of large RNA molecules provides much information for understanding the principles of structural organization of these complex molecules. Several in-depth analyses of nucleobase-centered RNA structural motifs and backbone conformations have been published based on this information, including a systematic classification of base pairs by Leontis and Westhof. However, hydrogen bonds involving sugar-phosphate backbone atoms of RNA have not been analyzed systematically until recently, although such hydrogen bonds appear to be common both in local and tertiary interactions. Here we review some backbone structural motifs discussed in the literature and analyze a set of eight high-resolution multi-domain RNA structures. The analyzed RNAs are highly structured: among 5372 nucleotides in this set, 89% are involved in at least one "long-range" RNA-RNA hydrogen bond, i.e., hydrogen bonds between atoms in the same residue or sequential residues are ignored. These long-range hydrogen bonds frequently use backbone atoms as hydrogen bond acceptors, i.e., OP1, OP2, O2', O3', O4', or O5', or as a donor (2'OH). A surprisingly large number of such hydrogen bonds are found, considering that neither single-stranded nor double-stranded regions will contain such hydrogen bonds unless additional interactions with other residues exist. Among 8327 long-range hydrogen bonds found in this set of structures, 2811, or about one-third, are hydrogen bonds entailing RNA backbone atoms; they involve 39% of all nucleotides in the structures. The majority of them (2111) are hydrogen bonds entailing ribose hydroxyl groups, which can be used either as a donor or an acceptor; they constitute 25% of all hydrogen bonds and involve 31% of all nucleotides. The phosphate oxygens OP1 or OP2 are used as hydrogen bond acceptors in 12% of all nucleotides, and the ribose ring oxygen O4' and phosphodiester oxygens O3' and O5' are used in 4%, 4%, and 1% of all nucleotides, respectively. Distributions of geometric parameters and some examples of such hydrogen bonds are presented in this report. A novel motif involving backbone hydrogen bonds, the ribose-phosphate zipper, is also identified.

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Polyol and sugar osmolytes can shorten protein hydrogen bonds to modulate function.

Publications

Polyol and sugar osmolytes can shorten protein hydrogen bonds to modulate function.

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