{"470231":{"#nid":"470231","#data":{"type":"news","title":"Large-Scale Modeling Shows Confinement Effects on Cell Macromolecules","body":[{"value":"\u003Cp\u003EUsing large-scale computer modeling, researchers have shown the effects of confinement on macromolecules inside cells \u2013 and taken the first steps toward simulating a living cell, a capability that could allow them to ask \u201cwhat-if\u201d questions impossible to ask in real organisms.\u003C\/p\u003E\u003Cp\u003EThe work could help scientists better understand signaling between cells, and provide insights for designing new classes of therapeutics. For instance, the simulations showed that particles within the crowded cells tend to linger near cell walls, while confinement in the viscous liquid inside cells causes particles to move about more slowly than they would in unconfined spaces.\u003C\/p\u003E\u003Cp\u003EThe research is believed to be the first to consider the effects of confinement on intracellular macromolecular dynamics. Supported by the National Science Foundation, the results are reported November 16 in the journal \u003Cem\u003EProceedings of the National Academy of Sciences\u003C\/em\u003E.\u003C\/p\u003E\u003Cp\u003EThe study is an interdisciplinary collaboration between \u003Ca href=\u0022http:\/\/www.cc.gatech.edu\/~echow\/\u0022\u003EEdmond Chow\u003C\/a\u003E, an associate professor in the Georgia Tech \u003Ca href=\u0022http:\/\/www.cse.gatech.edu\/\u0022\u003ESchool of Computational Science and Engineering\u003C\/a\u003E, and \u003Ca href=\u0022http:\/\/www.biology.gatech.edu\/people\/jeffrey-skolnick\u0022\u003EJeffrey Skolnick\u003C\/a\u003E, a professor in the Georgia Tech \u003Ca href=\u0022http:\/\/www.biology.gatech.edu\/\u0022\u003ESchool of Biology\u003C\/a\u003E. Their goal is to develop and study models for simulating the motions of molecules inside a cell, and also to develop advanced algorithms and computational techniques for performing large-scale simulations.\u003C\/p\u003E\u003Cp\u003E\u201cWe are setting the stage for what we need to do to simulate a real cell,\u201d said Skolnick. \u201cWe would like to put enough of a real cell together to be able to understand all of the cellular biochemical principles of life. That would allow us to ask questions that we can\u2019t ask now.\u201d\u003C\/p\u003E\u003Cp\u003EEarlier simulations, which produced much less fidelity, had assumed that movement within a cell was the same as movement in an unconfined space.\u003C\/p\u003E\u003Cp\u003ESkolnick compared the interior of a living cell to a large New Year\u2019s Eve party, perhaps even in Times Square.\u003C\/p\u003E\u003Cp\u003E\u201cIt\u2019s kind of like a crowded party that has big people and little people, snakes \u2013 DNA strands \u2013 running around, some really large molecules and some very small molecules,\u201d he said. \u201cIt\u2019s a very heterogeneous and dense environment with as much as 40 percent of the volume occupied.\u201d\u003C\/p\u003E\u003Cp\u003EThe simulations showed that molecules near the cell walls tend to remain there for extended periods of time, just as a newcomer might be pushed toward the walls of the New Year\u2019s Eve party. Motions of nearby particles also tended to be correlated, and those correlations appeared linked to hydrodynamic forces.\u003C\/p\u003E\u003Cp\u003E\u201cThe lifetimes of these interactions get enhanced, and that is what\u2019s needed there for biological interactions to occur within the cell,\u201d said Skolnick. \u201cThis lingering near the wall could be important for understanding other interactions because if there are signaling proteins arriving from other cells, they would associate with those particles first. This could have important consequences for how signals are transduced.\u201d\u003C\/p\u003E\u003Cp\u003EFor particles in the middle of the cell, however, things are different. These molecules interact primarily with nearby molecules, but they still feel the effects of the cell wall, even if it is relatively far away.\u003C\/p\u003E\u003Cp\u003E\u201cThings move more slowly in the middle of the cell than they would if the cell were infinitely big,\u201d Skolnick said. \u201cThis may increase the likelihood of having metabolic fluxes because you have to bring molecules around partners. If they are moving slowly, they have more time to react because intimate interactions by accident are unavoidable.\u201d\u003C\/p\u003E\u003Cp\u003EWhile the rate of activity slows quantitatively, qualitatively it is the same kind of motion.\u003C\/p\u003E\u003Cp\u003E\u201cSlowed motion is a double-edged sword,\u201d Skolnick explained. \u201cIf you happen to be nearby, it is likely that you are going to have interactions if you are slower. But if you are not nearby, being slower makes it difficult to be nearby, affecting potential interactions.\u201d\u003C\/p\u003E\u003Cp\u003EThe researchers also compared the activities of systems of particles with different sizes, finding that having particles of different sizes didn\u2019t make an appreciable difference in the overall behavior of the molecules.\u003C\/p\u003E\u003Cp\u003EWhile the simulations didn\u2019t include the DNA strands or metabolite particles also found in cells, they did include up to a half-million objects. Using Brownian and Stokesian physics principles, Skolnick and Chow considered what the particles would do within the confined spherical cell a few microns in diameter.\u003C\/p\u003E\u003Cp\u003E\u201cFrom the results of the computer simulations, we can measure things that we think might be interesting, such as the diffusion rates near the walls and away from the walls,\u201d said Chow. \u201cWe often don\u2019t know what we are looking for until we find something that forces us to ask more questions and analyze more data.\u201d\u003C\/p\u003E\u003Cp\u003ESuch simulations take a lot of computational time, so the algorithms used must be efficient enough to be completed in a reasonable time. The \u201cart\u201d of the algorithms is trading off fidelity with processing time. Even though the simulations were very large, they managed to study the actions of the confined particles for no more than milliseconds.\u003C\/p\u003E\u003Cp\u003E\u201cPart of the art of this is guessing what will be a reasonable approximation that will mimic the system, but not be so simple to be trivial or too complicated that you can\u2019t take more than a few steps of the simulation,\u201d Chow explained.\u003C\/p\u003E\u003Cp\u003EScientists, of course, can study real cells. But the simulation offers something the real thing can\u2019t do: The ability to turn certain forces on or off to isolate the effects of other processes. For instance, in the simulated cell Skolnick and Chow hope to build, they\u2019ll be able to turn on and off the hydrodynamic forces, allowing them to study the importance of these forces to the functioning of real cells.\u003C\/p\u003E\u003Cp\u003EResults from the simulation can suggest hypotheses to be confirmed or rejected by experiment, which can then lead to further questions and simulations.\u003C\/p\u003E\u003Cp\u003E\u201cThis becomes a tool you can use to understand real cells,\u201d said Chow. \u201cIt\u2019s a virtual system, and you can play all the games you want with it.\u201d\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EThis research was supported by the National Science Foundation under grant ACI-1147834. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Science Foundation.\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECITATION\u003C\/strong\u003E: Edmond Chow and Jeffrey Skolnick, \u201cEffects of confinement on models of intracellular macromolecular dynamics,\u201d (Proceedings of the National Academy of Sciences, 2015). \u003Ca href=\u0022http:\/\/www.pnas.org\/cgi\/doi\/10.1073\/pnas.1514757112\u0022\u003Ewww.pnas.org\/cgi\/doi\/10.1073\/pnas.1514757112\u003C\/a\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EResearch News\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EGeorgia Institute of Technology\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003E177 North Avenue\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EAtlanta, Georgia 30332-0181 USA\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMedia Relations Contact\u003C\/strong\u003E: John Toon (\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E) (404-894-6986).\u003Cbr \/\u003E\u003Cstrong\u003EWriter\u003C\/strong\u003E: John Toon\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EUsing large-scale computer modeling, researchers have shown the effects of confinement on macromolecules inside cells \u2013 and taken the first steps toward simulating a living cell, a capability that could allow them to ask \u201cwhat-if\u201d questions impossible to ask in real organisms.\u0026nbsp;\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"Researchers have shown the effects of confinement on macromolecules inside simulated cells."}],"uid":"27303","created_gmt":"2015-11-16 15:24:17","changed_gmt":"2016-10-08 03:19:58","author":"John Toon","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2015-11-16T00:00:00-05:00","iso_date":"2015-11-16T00:00:00-05:00","tz":"America\/New_York"},"extras":[],"hg_media":{"470211":{"id":"470211","type":"image","title":"Cell Visualization1","body":null,"created":"1449257160","gmt_created":"2015-12-04 19:26:00","changed":"1475895218","gmt_changed":"2016-10-08 02:53:38","alt":"Cell Visualization1","file":{"fid":"203882","name":"cell-simulation-1.jpg","image_path":"\/sites\/default\/files\/images\/cell-simulation-1_0.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/images\/cell-simulation-1_0.jpg","mime":"image\/jpeg","size":426829,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/cell-simulation-1_0.jpg?itok=Q-L9e2OX"}},"470221":{"id":"470221","type":"image","title":"Cell Visualization2","body":null,"created":"1449257160","gmt_created":"2015-12-04 19:26:00","changed":"1475895218","gmt_changed":"2016-10-08 02:53:38","alt":"Cell Visualization2","file":{"fid":"203883","name":"cell-simulation-2.jpg","image_path":"\/sites\/default\/files\/images\/cell-simulation-2_1.jpg","image_full_path":"http:\/\/hg.gatech.edu\/\/sites\/default\/files\/images\/cell-simulation-2_1.jpg","mime":"image\/jpeg","size":388966,"path_740":"http:\/\/hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/cell-simulation-2_1.jpg?itok=aPrSyNZG"}}},"media_ids":["470211","470221"],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"153","name":"Computer Science\/Information Technology and Security"},{"id":"143","name":"Digital Media and Entertainment"},{"id":"146","name":"Life Sciences and Biology"},{"id":"135","name":"Research"}],"keywords":[{"id":"532","name":"cell"},{"id":"148051","name":"cellular dynamics"},{"id":"11171","name":"Edmond Chow"},{"id":"11937","name":"Jeffrey Skolnick"},{"id":"148061","name":"macromolecules"},{"id":"2623","name":"modeling"},{"id":"7257","name":"visualization"}],"core_research_areas":[{"id":"39441","name":"Bioengineering and Bioscience"},{"id":"39431","name":"Data Engineering and Science"}],"news_room_topics":[{"id":"71881","name":"Science and Technology"}],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EJohn Toon\u003C\/p\u003E\u003Cp\u003EResearch News\u003C\/p\u003E\u003Cp\u003E\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E\u003C\/p\u003E\u003Cp\u003E(404) 894-6986\u003C\/p\u003E","format":"limited_html"}],"email":["jtoon@gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}