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Chemical Modification of the siRNA Seed Region Suppresses Off-Target Effects by Steric Hindrance to Base-Pairing with Targets.

ABSTRACT: Chemical modifications of 2'-O-methyl (2'-OMe) and locked nucleic acid (LNA) of the nucleotides in the seed region (positions 2-8) of the small interfering RNA (siRNA) guide strand significantly reduced seed-matched (SM) off-target effects. The siRNA with 2'-OMe modifications inhibited the expression of a completely-matched (CM) target gene, whereas that with LNA modifications did not inhibit the expression of the CM target. By computational predictions of conformational changes of siRNA by these modifications, we revealed that both modifications in the siRNA seed region reduce SM off-target effects by steric hindrance to base-pairing with target transcripts but LNA modifications also disturb the association of the siRNA guide strand with the Argonaute (AGO) protein by altering RNA conformation. Thus, chemical modifications of the siRNA guide strand, which alter steric conformation to disturb base-pairing with target transcripts but do not disturb the association with the AGO protein, may successfully suppress off-target effects without substantial loss of RNA silencing activity.

SUBMITTER: Iribe H

PROVIDER: S-EPMC5808362 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Chemical Modification of the siRNA Seed Region Suppresses Off-Target Effects by Steric Hindrance to Base-Pairing with Targets.

Iribe Hanna H Miyamoto Kengo K Takahashi Tomoko T Kobayashi Yoshiaki Y Leo Jastina J Aida Misako M Ui-Tei Kumiko K

ACS omega 20170512 5

Chemical modifications of 2'-O-methyl (2'-OMe) and locked nucleic acid (LNA) of the nucleotides in the seed region (positions 2-8) of the small interfering RNA (siRNA) guide strand significantly reduced seed-matched (SM) off-target effects. The siRNA with 2'-OMe modifications inhibited the expression of a completely-matched (CM) target gene, whereas that with LNA modifications did not inhibit the expression of the CM target. By computational predictions of conformational changes of siRNA by thes ...[more]

PMID: 29450406

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Project description:BackgroundIn computational structural biology, structure comparison is fundamental for our understanding of proteins. Structure comparison is, e.g., algorithmically the starting point for computational studies of structural evolution and it guides our efforts to predict protein structures from their amino acid sequences. Most methods for structural alignment of protein structures optimize the distances between aligned and superimposed residue pairs, i.e., the distances traveled by the aligned and superimposed residues during linear interpolation. Considering such a linear interpolation, these methods do not differentiate if there is room for the interpolation, if it causes steric clashes, or more severely, if it changes the topology of the compared protein backbone curves.ResultsTo distinguish such cases, we analyze the linear interpolation between two aligned and superimposed backbones. We quantify the amount of steric clashes and find all self-intersections in a linear backbone interpolation. To determine if the self-intersections alter the protein's backbone curve significantly or not, we present a path-finding algorithm that checks if there exists a self-avoiding path in a neighborhood of the linear interpolation. A new path is constructed by altering the linear interpolation using a novel interpretation of Reidemeister moves from knot theory working on three-dimensional curves rather than on knot diagrams. Either the algorithm finds a self-avoiding path or it returns a smallest set of essential self-intersections. Each of these indicates a significant difference between the folds of the aligned protein structures. As expected, we find at least one essential self-intersection separating most unknotted structures from a knotted structure, and we find even larger motions in proteins connected by obstruction free linear interpolations. We also find examples of homologous proteins that are differently threaded, and we find many distinct folds connected by longer but simple deformations. TM-align is one of the most restrictive alignment programs. With standard parameters, it only aligns residues superimposed within 5 Ångström distance. We find 42165 topological obstructions between aligned parts in 142068 TM-alignments. Thus, this restrictive alignment procedure still allows topological dissimilarity of the aligned parts.ConclusionsBased on the data we conclude that our program ProteinAlignmentObstruction provides significant additional information to alignment scores based solely on distances between aligned and superimposed residue pairs.

Dataset Information

Chemical Modification of the siRNA Seed Region Suppresses Off-Target Effects by Steric Hindrance to Base-Pairing with Targets.

Publications

Chemical Modification of the siRNA Seed Region Suppresses Off-Target Effects by Steric Hindrance to Base-Pairing with Targets.

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