Dataset Information

Computational investigation of RNA CUG repeats responsible for myotonic dystrophy 1.

ABSTRACT: Despite the importance of the knowledge of molecular hydration entropy (?Shyd) in chemical and biological processes, the exact calculation of ?Shyd is very difficult, because of the complexity in solute–water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estimating ?Shyd by means of combining the FEP approach and the scaled particle theory (or information theory) to separately calculate the electrostatic solute–water interaction term (?Selec) and the hydrophobic contribution approximated by the cavity formation entropy (?Scav), respectively. Decomposition of ?Shyd into ?Scav and ?Selec terms is found to be very effective with a substantial accuracy enhancement in ?Shyd estimation, when compared to the conventional full FEP calculations. ?Scav appears to dominate over ?Selec in magnitude, even in the case of polar solutes, implying that the major contribution to the entropic cost for hydration comes from the formation of a solvent-excluded volume. Our hybrid scaled particle theory and FEP method is thus found to enhance the accuracy of ?Shyd prediction by effectively complementing the conventional full FEP method.

SUBMITTER: Yildirim I

PROVIDER: S-EPMC4606397 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Computational investigation of RNA CUG repeats responsible for myotonic dystrophy 1.

Yildirim Ilyas I Chakraborty Debayan D Disney Matthew D MD Wales David J DJ Schatz George C GC

Journal of chemical theory and computation 20151001 10

Despite the importance of the knowledge of molecular hydration entropy (ΔShyd) in chemical and biological processes, the exact calculation of ΔShyd is very difficult, because of the complexity in solute–water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estim ...[more]

PMID: 26500461

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Project description:Myotonic dystrophy type 1 (DM1) is the most common type of adult muscular dystrophy caused by the expanded triple-nucleotides (CUG) repeats. Myoblast in DM1 displayed many defects, including defective myoblast differentiation, ribonuclear foci, and aberrant alternative splicing. Despite many were revealed to function in DM1, microRNAs that regulated DM1 via directly targeting the expanded CUG repeats were rarely reported. Here we discovered that miR-322/-503 rescued myoblast defects in DM1 cell model by targeting the expanded CUG repeats. First, we studied the function of miR-322/-503 in normal C2C12 myoblast cells. Downregulation of miR-322/-503 significantly hindered the myoblast differentiation, while miR-322/-503 overexpression promoted the process. Next, we examined the role of miR-322/-503 in the DM1 C2C12 cell model. miR-322/-503 was downregulated in the differentiation of DM1 C2C12 cells. When we introduced ectopic miR-322/-503 expression into DM1 C2C12 cells, myoblast defects were almost fully rescued, marked by significant improvements of myoblast differentiation and repressions of ribonuclear foci formation and aberrant alternative splicing. Then we investigated the downstream mechanism of miR-322/-503 in DM1. Agreeing with our previous work, Celf1 was proven to be miR-322/-503's target. Celf1 knockdown partially reproduced miR-322/-503's function in rescuing DM1 C2C12 differentiation but was unable to repress ribonuclear foci, suggesting other targets of miR-322/-503 existed in the DM1 C2C12 cells. As the seed regions of miR-322 and miR-503 were complementary to the CUG repeats, we hypothesized that the CUG repeats were the target of miR-322/-503. Through expression tests, reporter assays, and colocalization staining, miR-322/-503 was proved to directly and specifically target the expanded CUG repeats in the DM1 cell model rather than the shorter ones in normal cells. Those results implied a potential therapeutic function of miR-322/-503 on DM1, which needed further investigations in the future.

Dataset Information

Computational investigation of RNA CUG repeats responsible for myotonic dystrophy 1.

Publications

Computational investigation of RNA CUG repeats responsible for myotonic dystrophy 1.

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