H2020Индивидуална стипендия2015–2017

HoogsCG · Development of a multiscale modeling strategy to decipher how hybrid DNA/RNA triplexes and G-quadruplexes affect gene expression regulation

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2015-05-01 → 2017-04-30
Финансиране от ЕС: 195 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Компютърни модели анализират структурата и динамиката на сложни молекули, като например как се сгъват определени форми на ДНК. Това помага за по-точното разбиране на фундаментални биологични процеси и подпомага бъдещи биомедицински приложения.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Development of a multiscale modeling strategy to decipher how hybrid DNA/RNA triplexes and G-quadruplexes affect gene expression regulation

"Since this period report consist of the whole 24 months of the project, the continuous report contains the same information as the final report. This project deals with developing and applying computational tools to acurately describe complex biomolecular systems. Accurate, reproducible and well-converged computational results are still challenging, specially for systems containing large number of particles. This is crucially important to elucidate the interplay between structure and dynamics of large complex molecules in solution at atomistic level, for instance those responsible for maintaining genomic integrity. This project is important for society as it allows robust and accurate predictions on the behaviour of key players in fundamental biological processes, with direct implications with both basic research and potential biomedical applications. The overall objective was (1) to create a refined modelling strategy for describing nucleic acids, in the shape of new so-called force-field potentials, and incorporating computational strategies to enhance the description of such systems. Once this was developed, we used the refined set of potentials to (2) study the conformational landscape of DNA-protein complexes, as well as the folding and dynamics of quadruplex DNA. Finally, we (3) developed an accurate predictor for the stability of RNA-DNA2 triplexes, and applied it to predict the formation of such triplexes in vivo. As a final conclusion, we have successfully aided the development of a refined modelling strategy for nucleic acids (see publication entitled ""PARMBSC1: A refined force-field for DNA simulations"", and ""How accurate are accurate force-fields for B-DNA?""), co-developed a multi-scale approach to describe how ""Chromatin unfolding by epigenetic modifications (is) explained by dramatic impairment of internucleosome interactions"", as well as help determine the structure and dynamics of DNA-repair inducing protein RNF169, which recognises ubiquitylated chromatin."

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

This proposal concerns the study of non-canonical interactions in nucleic acids. These interactions, also known as non-Watson-Crick base pairing, involve single or multiple DNA or RNA strands and are increasingly recognized as having a variety of essential roles in replication forks, telomeres, and gene regulation. Since these processes occur on spatial and time scales beyond the reach of current computational capabilities, we propose to develop an innovative coarse-grain approach to describe them. This approach will tackle an important and yet unmet challenge - the correct description of non-canonical interactions at near-atomic resolution in large-scale nucleic acids. The model will be derived from exhaustive classical all-atom molecular dynamics simulations and will be validated against experimental observables including nuclear magnetic resonance spectroscopy and small angle x-ray scattering. It will be used to describe non-canonical interactions – including Hoogsteen base pairs, which are the building blocks of triplex and quadruplex structures – and will incorporate the effects of epigenetic marks on DNA. The model will enable the description of the sequence dependent mechanical properties of guanine quadruplexes and triplex folds on temporal and spatial scales beyond the reach of current methods. As such, it will allow us to investigate the formation and dynamics of long triplex hybrids of DNA and RNA, the behaviour of long-non-coding RNAs interacting with naked DNA, and the effects of non-canonical interactions in systems relevant to chromatin. Thus, this model will be useful to predict and understand the molecular bases of fundamental open questions in biology and has a potential impact in molecular medicine and the pharmacological industry. Overall, this approach will provide an invaluable theoretical tool to describe nucleic acid structures and dynamics, contributing to the description and prediction of a wide range of genetic and epigenetic processes.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE · CAMBRIDGEКоординаторОбединеното кралство