人體每一個(gè)細(xì)胞里，都有串聯(lián)起來可以長(zhǎng)達(dá) 12英尺 的DNA分子,，還好這些帶有遺傳訊息的分子,，可以緊密的纏繞，相互糾結(jié)在一起,，好擠進(jìn)極其微小的細(xì)胞里,，然而科學(xué)家深感困惑的，是細(xì)胞到底要如何的調(diào)控,，才能準(zhǔn)確的使要活動(dòng)的核酸序列露出,，而順利的進(jìn)行基因的表達(dá)，最近由美國維吉尼亞技術(shù)學(xué)院 (Virginia Tech)的科學(xué)家,，發(fā)表了一篇刊登于最新一期生物物理學(xué)期刊 (Biophysical Journal)的論文,，模擬了長(zhǎng)鏈 DNA分子可能存在的活動(dòng)，可能回答了這個(gè)長(zhǎng)久以來困惑科學(xué)家的迷團(tuán),。
這個(gè)研究計(jì)劃,，主要由該校基因生物信息與生物計(jì)算學(xué)學(xué)程 (Genetics, Bioinformatics and Computational Biology Program)的博士班學(xué)生 Jory Zmuda Ruscio所參與,，據(jù)了解 Jory領(lǐng)導(dǎo)的研究人員,，利用了一個(gè)新的研究方法，并且搭配該大學(xué)所擁有的System X 超級(jí)計(jì)算機(jī),，就先前相關(guān)數(shù)據(jù)的了解,，這部超級(jí)計(jì)算機(jī)擁有1100 個(gè)中央處理器，透過大量DNA 數(shù)據(jù)的輸入,，可以架構(gòu)出像長(zhǎng)鏈蟲狀的核酸結(jié)構(gòu)分子,，而高功能多達(dá)1100個(gè)中央處理器，則可以高速的模擬運(yùn)算,，解析出 DNA巨型結(jié)構(gòu)最佳的活動(dòng)原型。這次的研究計(jì)劃,，參與的科學(xué)家選定一段包括 147個(gè)核酸鹽基的序列,，就先前的了解，這一段序列可以生成一個(gè)包括 8個(gè)蛋白質(zhì)所組成的復(fù)合體,，而這一段核酸的活動(dòng),，就可以具體而微的放大細(xì)胞里，基因真實(shí)的運(yùn)作現(xiàn)象,。
研究人員發(fā)現(xiàn)這次放大到原子層級(jí)的核酸分子模型 其所呈現(xiàn)的彈性 遠(yuǎn)超過過去科學(xué)家所理解的范圍,，相關(guān)的科學(xué)家認(rèn)為這種核酸運(yùn)作的分子模型，有助于我們真正的掌握DNA 活動(dòng)的真相,，而這很可能是未來破解許多原因仍然未知疾病的線索,。
英文原文：
First molecular simulation of a long DNA strand shows unexpected flexibility
It turns out that sequencing the human genome ?determining the order of DNA building blocks -- has not completely cracked the code of how DNA directs various cellular processes. In addition to the sequence of the base pairs, the instructions are in the packaging ?how DNA is folded within a cell.
Virginia Tech researchers used novel methodology and the university System X supercomputer to carry out what is probably the first simulation that explores full range of motions of a DNA strand of 147 base pairs, the length that is required to form the fundamental unit of DNA packing in the living cells -- the nucleosome. Contrary to a long-held belief that DNA is hard to bend, the simulation shows in crisp atomic detail that DNA is considerably more flexible than commonly thought.
The research is published in the December issue of the Biophysical Journal, in the article Computational Study of Nucleosomal DNA Flexibility,?by Jory Zmuda Ruscio of Leesburg, Va., a Ph.D. student in the Genetics, Bioinformatics and Computational Biology Program at Virginia Tech, and Alexey Onufriev of Blacksburg, assistant professor of computer sciences and physics at Virginia Tech. They have been invited to do a platform presentation at the 51st Biophysical Society Annual Meeting in Baltimore in March.
There is about 12 feet of DNA in a human cell but it is packaged into nucleosomes ?lengths of 147 base pairs each wrapped around eight special proteins. A nucleosome looks kind of like the lumpy beginning of a rubber-band ball. Or maybe more like a lumpy worm coil. Uncoiled, the worm wiggles, flexes, and even kinks, according to a simulation performed on System X.
As we know from watching forensic detective shows on TV, the DNA in all of an individual抯 cells is identical. The DNA in fingernail cells is exactly the same as in muscle. Yet the cells are different. This is because, roughly speaking, the DNA in different cell types is packed differently and the complexes it forms with the surrounding proteins are in different positions, so only the relevant part of the code can be read at a time,?said Onufriev. Although nobody knows exactly how it happens, you can imagine reading only what you can see on a part of a crumpled newspaper.
The traditional view is that DNA is relatively rigid and that considerable energy is required when it needs to be bent to form protein-DNA complexes. However, recent experiments (Nature, Aug. 17, 2006) have begun to challenge that view. The famous double-helix may be much more flexible than previously thought,?said Onufriev.
The Virginia Tech research responded to this debate. Using 128 of System X 1,100 processors, the research resulted in a System X movie revealing DNA wiggling like a worm, showing greater flexibility than expected from the traditional view. The DNA packing in the nucleosome is also found to be surprisingly loose. The implication is that it may not cost much energy to bend the DNA ?even to bend sharply,?said Onufriev.
The methodology that is making it possible is based on the so-called 搃mplicit solvent?approach being developed by Onufriev. Biology does not happen in a vacuum,?he said. 揥e are 75 percent water, and the effect of the water environment must be taken into account when studying biomolecules.
Previous simulations were often slowed because they accounted for the water that is present in living systems. For instance, in early studies of protein folding, only a few percent of the computing effort was being spent on the activity of the protein while the rest accounted for the activity of the surrounding fluids. The implicit solvent?approach accounts for the role of water on average, but the movements of individual water molecules are not predicted, freeing computation capacity for simulation of whatever protein is being studied.
Experiment cannot always probe atomic detail of living molecules because they are too small and often move too fast, said Onufriev. But we can combine computational power with good algorithms to simulate these motions at high (atom-scale) resolution.
It is an exciting time to do molecular modeling,?he said. The computing power and the methodology have come to the point that we can begin to fully probe biology on timescales very relevant to living things ?such as DNA packing.
Virginia Tech's System X supercomputer was critical to this research, he said. It was the combination of its sheer compute power with the algorithmic advantages that made it possible to run molecular simulations on that scale.
So far, the Virginia Tech research team addressed the question of how flexible the DNA is, which is only a small piece of the second part of the genetic code?puzzle, Onufriev said. However, this small piece should pave the way to addressing bigger questions, such as exactly how is the tightly packed genetic content read by cellular machines".
揂tomic level simulations can complement experimentation and narrow competing theories,said Onufriev. 揊or systems as large as the nucleosome, simulations using virtual water may be the only practical way to estimate the stability of various confirmations,he said.
How DNA bends and flexes is critical for many cellular processes including cell differentiation and DNA replication. Although also observed in recent experiments, this unusual DNA flexibility is still unexplained. "Now seeing that DNA is not as hard to bend may lead to radical changes in our perspective," said Onufriev. "We are using these detailed pictures to see exactly how DNA bends and to understand the details of the mechanism behind it, something that is very hard or impossible to do experimentally."
Onufriev and his group of biochemistry, physics, biology, and other computer science researchers received a $1.1 million grant from the National Institutes of Health to develop high performance computing methodology to create molecular models and to probe in atomic detail the mechanisms of biology.
The purpose of the NIH award is to develop the methodology for computer simulations of complex biological processes and address the question of the atomic mechanism of DNA flexibility, Onufriev said. 揟his research may not only provide fundamental insights into how life works at the molecular level, but also has applications in drug discovery and in particular for rational drug design, which is an important consideration for the NIH.
