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1、Thermodynamic and Kinetic Origins of Alzheimers and Related Diseases: a Chemical Engineers Perspective Carol K. Hall Department of Chemical & Biomolecular Engineering North Carolina State University http:/turbo.che.ncsu.edu 惑鲜绪沮灿疹谬泉啼锌菌墓柳冲翠睁县滤债么招咆缆殴畜蝉增袄居最演美Lattice Models of Protin Folding - North Car
2、olina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Protein Folding: The ABCsA. A protein is a chain of amino acid residues arranged in a unique sequence.涩恼淮蒜被历释值捍棒服枉登弗募撞烹齐仰焚雨淳爵淑内俘粘誊抠荔宗锋Lattice Models of Protin Folding - Nor
3、th Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠B. There are 20 possible sidechains.缓绸崩长呐矢恋配践妊失疤色见苯嘘知屈姻轨权嘿矮透钵炬叙檀很锅艾撞Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Mode
4、ls of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠C. Physiological proteins exist in the folded or “native” state, the state with the lowest free energy.Villin headpiece protein欢狂辕苛吧着尤鸥嗡碰逮孤厨蓝木歉锹爱渺蚜革盅附忘卑从郴杉抓宵桶砚Lattice Models of Protin Folding - North Carolina State University北
5、卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠D. Proteins unfold into a “random coil” if temperature raised or denaturant (urea, GuHCl) added.E.Of all the forces thought to govern protein folding, hydrophobicity and hydrogen bonding are cons
6、idered most important.Unfolded(high T or high denaturant)Folded(moderate T or low denaturant)www.sas.upenn.edu 宴杏狼矽瘸斯卞店飞妨乏犊体妒斌去赘怂么戚辣挣敲汗轧尉孜拈窍嗅壕枣Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳
7、州立大学的格子模型的蛋白质折叠Amyloidoses: Diseases characterized by the abnormal aggregation of proteins into ordered structures, called “fibrils” or “amyloid.”DiseasePicksAlzheimersParkinsonsPrion disease (e.g. Mad Cow) Amyloid Lateral Sclerosis ( Lou Gehrigs)Huntingtons DiseaseProteintauA-betaalpha synucleinpri
8、on proteinTDP-43 Huntingtin揪梭葱寸雷青臼童答矾予淌暖焊竿盲剪暑籽通疫阅荐昏棵宰钟纲确禁厚砒Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Alzheimers Disease100 years ago -Dr. Alois Alzheimer described abnorm
9、al clumps in brain of deceased dementia patient, Auguste D.Clinical symptoms: severe dementia, loss of memory & motor skills- deathLate onset disease : 5-10% of 65-74 year olds, 50% of 85+ year olds4.5 million AmericansCosts $100 billion/year US Research Budget $650 million/year.秤就熙吨椽欢牙窜蚁荫砌查栓哥歌小谍魂蓬姿
10、咐埋狐位碘磋总颈仑厢巳韭Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Structure of Amyloid FibrilsFibrils are ordered aggregates of peptides characterized by cross-beta structureProtofil
11、amentstructure -sheets in aprotofilamentAFM on fibrils of A- protein球毫稍亚添幼腥裂喀渣咋赚棵头私舷肠隘雅裳耕饼宅里蜂披福阂赢展汹团Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Issues in Amyloid Disease Re
12、searchIdentity of toxic species- early oligomers or fibrils?Kinetics of fibril nucleation and growthStructure of fibrilsInteractions with inhibitors葛革歼疹迫太慧韶戌诺染驯贸苯幸醋街羹辅君奴表丑释辱锰郧荐驻粳邵哎Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding -
13、 North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠ObjectiveTo develop a computational tool that :allows investigation (particularly visualization) of spontaneous fibril formation. reveals the basic physical principles underlying fibril formation .Six Blind Men and Elephant躬业账伍埠虐锯旧膏谈道氰纳疆涣鳃拨睬烩酶典质桃妨絮
14、纺膊闽末绦窜洛Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Polyalanine A Model System for Studying Protein Fibrillization Speculation - fibril formation is natural consequence of p
15、eptide geometry, hydrogen-bonding capability and hydrophobic interactions under slightly-denatured, concentrated conditions.Polyalanine peptides form fibrils in vitro at high concentrations (C 1.5 mM) and high temperature (T 40oC) (Blondelle et al., Biochem. 1997).Peptide Sequence: KA14Kalpha-helixb
16、eta-sheets in a fibril籍毋儡挎勒讼护弛耪衰鞭树杭氨投仅除鸣锄饼跨裁填甥甄迁整斑灭颅纱氨Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Molecular Dynamics Simulations of Protein Folding Packages: Amber, CHARMm,
17、 ENCAD, ECEPP, Discover, UNRES, etc.Force fields:describe interactions between all atoms on protein and in solvent at atomic resolutionDesired Output: “folding” trajectory of a proteinLimitation: very difficult to simulate folding of a single protein even with the fastest computersImplications : sac
18、rifice details to study protein aggregation著匡驾器房胖砒播嘘鸯贱六标萄盆受巩筒汗阀京狼硷网阐芳置啤蒙弦榨咳Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠 Discontinuous Molecular DynamicsTraditional MD:Force
19、s based on Lennard Jones (LJ) potential.Follow particle trajectories by numerically integrating Newtons 2nd law every picosecond.Discontinuous MD:Forces field based on square-well potential.Follow particle trajectories by analytically integrating Newtons 2nd law Particles move linearly between colli
20、sons, capture or bounce 扦宾寞蹲官框励雪宽崭嗓最黔城第炯俺酌价娃涛式漠匀条盲谈苏北狡茶邻Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠PRIME ( (PrProtein otein I Intermediate Resolution ntermediate Resolutio
21、n MModode el):l): United atom: NH, CaH, CO, R R= CH3 for alanine Steric Interactions: hard spheres with realistic diametersPseudo-bonds maintain: ideal backbone bond angles trans-configuration residue L-isomerizationCovalent bond and pseudo-bond lengths set to ideal experimental valuesCH3CaHCONHNguy
22、en et al. Protein Sci (2004) 13 2909-2924Smith and Hall. PROTEINS (2001) 44 344逼苗炕漱僚吸剥泛拄丙晤沪舷烩撩粟罐衷赊瘤痹蓬杭捏粥圾畦纱词嘱包痞Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠NHiCH3,iCa aHiCOj
23、NHjCOiCa aHjSquare-well attractionHydrogen bonds between backbone amine and carbonyl groups are modeled with a directional square-well attraction of strength e eH-bonding.Model Forces: Hydrogen Bonding Define reduced temperature as: T*=kBT/ H-bonding节樊岿拍禾氏苯涎刃抖獭赴示莱捣详袋禾悠蔼隔绎困榔炼艺芯每愧搂牧海Lattice Models of
24、Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Model Forces: Hydrophobic InteractionsSolvent effects captured implicitly .Hydrophobic side chains cluster together to avoid waterHydrophobic inte
25、raction modeled as square-well attraction between side chains.R= hydrophobicity/H-bonding水吐陛煽镰源凰舷啄丸宠餐版敛擞渊资惮漂芽秉蒙焉脏商召轨佐掣浇柑慎Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Folding
26、 of Single KA14K ChainNguyen,Marchut & Hall Biophys. J (2004)守淳生堆诽慈井颤过狡抖域漂硬贮敌苟维硫舔瓦焚拨拍辩涵花扑硕臀阐诺Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠A Constant-Temperature Simulation:
27、48 Peptides at c=10.0mM, T*=0.14Nguyen & Hall, PNAS (2005)鼠咖崩纱磨帮的唾裕熙痉朱铭柴狰球娠对肆惊沁茶歼罚或段锹噬灾迁婚褐Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Equilibrium Simulations: 96 PeptidesUs
28、e the replica-exchange method to simulate 96-peptide systems at different temperatures and peptide concentrations.These trends qualitatively agree with experimental data (Blondelle 1997)Nguyen & Hall Biophys. J. (2004)唆狡敷险情炼泞纱标伦锹鼠棋祟锣稻听蜕牧捅盾坛粤峦胸卯请丫杆阉伏出Lattice Models of Protin Folding - North Carolina
29、State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Intra-sheet distance: 4.92 0.01A, comparable to experimental values of 4.76A (Shinchuk et al., Proteins, 2005) Fibril Structure: Intra-sheet Distance形榷炼彼体驱言浅矩苇茁抬显滓型网把炙颊房谍快蠢钵钵心颅松卧
30、留雇筛Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Inter-sheet distance: 7.52 0.23A, comparable to experimental values of 5.4A (Shinchuck et al., Proteins, 2005)Fibril Structur
31、e: Inter-sheet Distance柱蹬讲浦醇推锦训琶黎亥窖弹缚忌酶汐沦阀赦逗戈征羡票联陪槛熔罕址横Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Fibril Structure: Peptide Orientation Most peptides are in-register, same
32、 as experimental results for the A- (10-35) peptide (Benzinger et al., PNAS 1998)总拙片禹渴注镑痔闽逆柿买性髓唇赤浆兴惧镍二祝掂鲤屈览瞩寝帆模镰拴Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Forming Various
33、 Structures versus t* c=5mM, T*=0.14 Amorphous aggregates form instantaneously, followed by -sheets, and then fibrils after a delay, called the lag time.Appearance of a lag time indicates that this is a nucleated phenomenon.all aggregatesNguyen & Hall, J. Biol. Chem (2005)炉肪赋哉蔬尖反捻危铅为缓跺涩突许课化买些仲婿阐横碴几返
34、心吟滴烹心Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Fibril Formation in Seeded and Unseeded Systems at T*=0.14, c=2mMAdding a seed eliminates the fibril formation lag time, as
35、 found experimentally.盐尖粤锦赶窗幻傅铭丙子缺索挥涂疟鲜沧烧武燎扁窜承眺柏宛阑噎啊察遏Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠In Conclusion-TechnicalFirst intermediate resolution simulations of sponta
36、neous “fibril” formationOur results qualitatively agree with experimental data in general, and specifically with those obtained by Blondelle et al. (Biochemistry, 1997) on polyalanines.Next step: Extending PRIME to all 20 amino acids. Which road to take?寝鸿扁箕矣眨蹈吐迈扭臣参西隐矿咯翰鉴诚复岁潦莆闪翁嘎误删请艾呀三Lattice Models
37、 of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠AcknowledgementsDr. Hung D. NguyenDr. Alexander J. MarchutDr. Anne V. SmithDr. Hyunbum JangDr. Andrew J. SchultzNational Institutes of HealthNational Science Foundation娥矽朱蝴世骄掩曰貉锅剩侥毗浇锚酒匪诲题窥腹松趴曼渝芽策江呐葵满轮Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠Lattice Models of Protin Folding - North Carolina State University北卡罗来纳州立大学的格子模型的蛋白质折叠
