![]() ![]() While the binding preferences between standard nucleobases and amino acids have in general been well studied 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, much less is known about how these preferences change in the case of typical nucleobase modifications, with most work focusing on the overall impact of modifications on the affinities between complete nucleic acids and proteins 21, 22, 23, 24. Importantly, such recognition also directly depends on the intrinsic binding preferences between the individual nucleobases and amino acids in different environments 11. In general, DNA and RNA recognition by proteins depends on different environmental, structural and dynamical determinants. However, less is known about the atomistic mechanisms behind such phenotypic changes and, in particular, how nucleobase modifications affect the interactions between the modified nucleic acids and protein readers, which detect them. Notably, the impact of the DNA/RNA modifications on gene expression and transcript stability has mostly been studied from the perspective of how the change in their genomic or transcriptomic patterns affects the cellular or organismic phenotype 3, 5. In RNA, nucleobase modifications affect different molecular processes, including mRNA transcription, splicing, export, translation and degradation 3, 7, 8, 9, 10. In DNA, modified nucleobases play key roles in cell differentiation, aging and disease development by either remodeling chromatin structure or affecting directly the DNA/protein interactions 1, 2, 4, 5, 6. Modifications of standard DNA/RNA nucleobases greatly amplify the amount of information encoded in nucleic-acid sequences and are associated with epigenetic regulation of gene expression and modulation of transcript stability 1, 2, 3. Our results contribute towards establishing a quantitative foundation for understanding, predicting and modulating the interactions between modified nucleic acids and proteins at the atomistic level. For those two modified bases, the effect is more nuanced and manifests itself primarily at the level of absolute changes in the binding free energy. Conversely, we show that the relative ordering of sidechain affinities for 5hmC and m 6A does not differ significantly from those for their precursor bases, cytosine and adenine, respectively, especially in the low dielectric environment. Our analysis identifies protein side chains that are highly tuned for detecting cytosine methylation as a function of the environment and can thus serve as microscopic readers of epigenetic marks. We verify the derived affinities by comparing against a comprehensive set of high-resolution structures of nucleic-protein complexes involving 5mC. We derive here the absolute binding free energies and analyze the binding modalities between key modified nucleobases 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC) and N 6-methyladenine (m 6A) and all non-prolyl/non-glycyl protein side chains using molecular dynamics simulations and umbrella sampling in both water and methanol, the latter mimicking the low dielectric environment at the dehydrated nucleic-acid/protein interfaces. We conjecture that this thermal hierarchy reflects an underlying temporal order, and that side-chain ordering facilitates the search for the correct backbone topology.Covalent modifications of standard DNA/RNA nucleobases affect epigenetic regulation of gene expression by modulating interactions between nucleic acids and protein readers. Our results indicate a thermal hierarchy of ordering events, with side-chain ordering appearing at temperatures below the helix-coil transition but above the folding transition. ![]() ![]() Rather, side-chain ordering is spread over a wide temperature range. B, 111 (2007) 4244) we do not find collective effects leading to a separate transition. In contrast to earlier studies on homopolypeptides (Wei et al., J. Concepts of circular statistics are introduced to analyze side-chain fluctuations. For this purpos e we have performed multicanonical simulations of the villin headpiece subdomain HP-36, an often used to y model in protein studies. Wei and 2 other authors Download PDF Abstract: We investigate the relation between backbone and side-chain ordering in a small protein. Download a PDF of the paper titled Backbone and Sidechain Ordering in a small Protein, by Y. ![]()
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