第二章 蛋白質(zhì)的結(jié)構(gòu)生物信息學(xué)基礎(chǔ)

1、第二章蛋白質(zhì)的結(jié)構(gòu)生物信息學(xué)基礎(chǔ)學(xué)習(xí)蛋白質(zhì)結(jié)構(gòu)生物信息學(xué)的建議上機實習(xí)尤其重要!可以方便地使用計算機(班級干部能否請丁小瓊老師安排上機實習(xí)時間?)要在linux操作系統(tǒng)下運行軟件(Docking and MDs)(武漢大學(xué)計算中心是否有條件?)單個蛋白質(zhì)空間結(jié)構(gòu)蛋白質(zhì)-蛋白質(zhì)復(fù)合物結(jié)構(gòu)蛋白質(zhì)的動態(tài)構(gòu)象第二章蛋白質(zhì)的結(jié)構(gòu)生物信息學(xué)基礎(chǔ)一、蛋白質(zhì)的初級結(jié)構(gòu)二、蛋白質(zhì)的二級結(jié)構(gòu)三、蛋白質(zhì)的三級結(jié)構(gòu)蛋白質(zhì)的初級結(jié)構(gòu)-氨基酸結(jié)構(gòu)共性碳原子20種氨基酸氨基酸的構(gòu)象與性質(zhì)Hydrophobic-aliphatic amino acids 原子標記Hydrophobic-aromatic amino acid

2、sNeutral-polar amino acidsAcidic amino acidsBasic amino acidsConformationallyimportant amino acids構(gòu)建了80余個突變體,蛋白質(zhì)殘基數(shù)太多,不宜做CD,為什么?2. Chargesalt bridge (or 'ion pair')3. Polarity主鏈、側(cè)鏈、溶劑分子兩兩之間形成氫鍵Ser, Thr, Asn, GlnTyr, Trp,Asp, Glu, Lys, Arg, His4. Hydrophobicity在蛋白質(zhì)折疊和結(jié)構(gòu)穩(wěn)定中起重要作用！Gly, Ala, Val,

3、 Leu, ILe, Met, Cys, Pro,Tyr, Trp,Implications of PrimaryStructurePrimary Structure Determines All Higher Levels of StructureHomologyThe Three-dimensional Structure of Proteins is More Highly Conserved than the Primary Structure第二章蛋白質(zhì)的結(jié)構(gòu)生物信息學(xué)基礎(chǔ)一、蛋白質(zhì)的初級結(jié)構(gòu)二、蛋白質(zhì)的二級結(jié)構(gòu)三、蛋白質(zhì)的三級結(jié)構(gòu)Types of SecondaryStructur

4、eAlphahelicesBeta sheets TurnOther蛋白質(zhì)的高級結(jié)構(gòu)結(jié)構(gòu)生物學(xué)的意義結(jié)構(gòu)生物學(xué)在“后基因組時代”生物學(xué)中的地位：在蛋白質(zhì)一級結(jié)構(gòu)序列信息基本已知后，三維原子結(jié)構(gòu)已成為下一步也是最后一步為全面深入理解生命奧秘所必需的結(jié)構(gòu)信息。因此，結(jié)構(gòu)基因組學(xué)應(yīng)運而生。蛋白結(jié)構(gòu)以及大分子相互作用是揭示生物功能及研究人類疾病分子機理的基本前提。大分子結(jié)構(gòu)也是合理藥物設(shè)計和蛋白質(zhì)工程等應(yīng)用研究的重要基礎(chǔ)。第二章蛋白質(zhì)的結(jié)構(gòu)生物信息學(xué)基礎(chǔ)一、蛋白質(zhì)的初級結(jié)構(gòu)二、蛋白質(zhì)的二級結(jié)構(gòu)三、蛋白質(zhì)的三級結(jié)構(gòu)蛋白質(zhì)結(jié)構(gòu)決定功能離子通道的結(jié)構(gòu)選擇性過濾離子離子通道是的開/關(guān)不同離子通道選擇過濾不同的

5、離子離子通道與疾病cardiac arrhythmias (心律失常)Diabetes（糖尿?。﹉ypertension （高血壓）angina pectoris（心絞痛）Epilepsy（癲癇）Alzheimers Disease（老年性癡呆）Parkinsons （帕金森氏?。㏒chizophrenia（精神分裂癥）部分與疾病相關(guān)的膜通道亞型Nature, 2006；Nature, 2007鉀通道時空表達差異與自身免疫性疾病系統(tǒng)性紅斑狼瘡多發(fā)性硬化癥類風(fēng)濕性關(guān)節(jié)炎蛋白質(zhì)結(jié)構(gòu)是動態(tài)變化的_人也是機器人！鉀通道結(jié)構(gòu)與開放與關(guān)閉PNAS, 2006HIV-1與宿主細胞的膜融合非共價相互作用穩(wěn)定蛋

6、白質(zhì)的結(jié)構(gòu)氫鍵的作用疏水作用Potassium channel: mKv1.2 structureScience, 2007蛋白質(zhì)折疊類型是有限的有限的的結(jié)構(gòu)單元蛋白質(zhì)結(jié)構(gòu)的測定X射線晶體學(xué)(X-ray Crystallography)晶體結(jié)構(gòu)(不含H)核磁共振(NMR)溶液結(jié)構(gòu)(含H)NMR1D 1H spectrum of a small proteinNMRspin coupling: protein 2D 1H spectrumNMRnot one, but many structures!NMRadvantage: protein in its natural environment

7、 advantage: information about dynamics/foldingdisadvantage: size limitation (about 30 kD)disadvantage: structure not completely defined disadvantage: complicated experiments requireexotic nucleiX-ray Crystallographypurify protein to 99% puritygrow small crystals from the pure proteinmeasure X-ray di

8、ffraction data from the crystal solve the "phase problem"build model in the electron density mapGrowing a CrystalX-ray CrystallographyDiffractionX-ray Crystallographyan electron density map with a protein modelX-ray Crystallographyadvantage: high resolution image of all atomsin your proteinadvantage: no size limitations (virus particles!) advantage: easy to study complexes disadvantage: you NEED a crystaldisadvantage: pro