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Computational backbone mutagenesis of Abeta peptides: probing the role of backbone hydrogen bonds in aggregation.

ABSTRACT: Using replica exchange molecular dynamics (REMD) and united atom implicit solvent model we examine the role of backbone hydrogen bonds (HBs) in Abeta aggregation. The importance of HBs appears to depend on the aggregation stage. The backbone HBs have little effect on the stability of Abeta dimers or on their aggregation interface. The HBs also do not play a critical role in initial binding of Abeta peptides to the amyloid fibril. Their elimination does not change the continuous character of Abeta binding nor its temperature. However, cancellation of HBs forming between incoming Abeta peptides and the fibril disrupts the locked fibril-like states in the bound peptides. Without the support of HBs, bound Abeta peptides form few long beta-strands on the fibril edge. As a result, the deletion of peptide-fibril HBs is expected to impede fibril growth. As for the peptides bound to Abeta fibril the deletion of interpeptide HBs reduces the beta propensity in the dimers making them less competent for amyloid assembly. These simulation findings together with the backbone mutagenesis experiments suggest that a viable strategy for arresting fibril growth is the disruption of interpeptide HBs.

SUBMITTER: Takeda T

PROVIDER: S-EPMC2862262 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Computational backbone mutagenesis of Abeta peptides: probing the role of backbone hydrogen bonds in aggregation.

Takeda Takako T Klimov Dmitri K DK

The journal of physical chemistry. B 20100401 14

Using replica exchange molecular dynamics (REMD) and united atom implicit solvent model we examine the role of backbone hydrogen bonds (HBs) in Abeta aggregation. The importance of HBs appears to depend on the aggregation stage. The backbone HBs have little effect on the stability of Abeta dimers or on their aggregation interface. The HBs also do not play a critical role in initial binding of Abeta peptides to the amyloid fibril. Their elimination does not change the continuous character of Abet ...[more]

PMID: 20302321

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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.

Dataset Information

Computational backbone mutagenesis of Abeta peptides: probing the role of backbone hydrogen bonds in aggregation.

Publications

Computational backbone mutagenesis of Abeta peptides: probing the role of backbone hydrogen bonds in aggregation.

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