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生物核磁共振波谱学 NMR in Biological Science 闫永彬 博士 Yong-Bin YAN, Ph.D. 清华大学 THNMR YAN 生物科学与技术系 Why learn NMR? THNMR YAN A remarkable field One of the two leading technologies in structural biology Great contributions to biology A special window to the development of modern structural biology and biophysics 1.1 A Remarkable Field Nobel Prize 1943年 O. Stern 物理学奖 — 测定质子磁矩 1944年 I. I. Rabi 物理学奖 — 测定磁矩的共振方法 1952年 F.Bloch & E. M. Prucell 物理学奖 — 发现核磁共振现象 1991年 R. R. Ernst 化学奖 — FT NMR & 2D NMR THNMR YAN 1.2 One of the two leading technologies in structural biology THNMR YAN Ref: Wuthrich K. Nature Structural Biology 5, 492 - 495 (1998) 1.2 One of the two leading technologies in structural biology PDB HOLDINGS (30-JUL-2001) MOLECULE TYPE EXPEREME NTAL TECHNIQU E X-RAY DIFFRAC TION AND OTHER NMR THEORET ICAL MODELIN G TOTAL THNMR YAN PROTEINS, PEPTIDES, AND VIRUSES PROTEIN/NUCLEIC ACID COMPLEXES NUCLEIC ACIDS CARBOHYD RATES TOTAL 11,630 556 580 14 12,780 1,918 73 383 4 2,378 288 19 23 0 330 13,836 648 986 18 15,488 Ref: PDB ANNUAL REPORT, July 2000 - June 2001 Molecular weight distribution of the NMR structures deposited in the Brookhaven PDB as of December 1997. Guntert P. Q Rev Biophys, 31:145-237 (1998). THNMR YAN 1.3 Great contributions to biology solution structures at atomic resolution in semiphysiological conditions dynamic properties and the properties of partially folded or unfolded proteins weak interactions between macromoloecules and ligands a practical approach to drug design Ref: Wagner G. Nature Structural Biology. 4: 841-844 (1997) THNMR YAN 1.4 Milestones NMR 1946 - the first spectra of solid compounds 1957 - the first spectra of a protein - RNase A 1982 - the first protein spectra was assigned 1985 - the first solution structure of a protein 1997 - 924 NMR structures in PDB Today - over 2,378 structures in PDB X-ray 1913 - the first diffraction patterns of crystals were reported 1934 - the first protein crystallized and examined - pepsin 1960 - the first protein crystal structures - myoglobin, hemoglobin 1997 - 5012 crystals structures in PDB Today - over 12,780 structures in PDB THNMR YAN Ref: Wagner G. Nature Structural Biology. 4: 841-844 (1997) PBD ANNUAL REPORT, 2001 1.4 Milestones X-ray: 25 years older than NMR • more order, more mature NMR: still in a developmental stage • major improvements are still being made Incomplete view using only one single techniques Ref: Wagner G. Nature Structural Biology. 4: 841-844 (1997) THNMR YAN NMR Applications —— A-Z THNMR YAN Agriculture; Animal Behavior; Analytic Chemistry Biomolecule NMR; Biophysics; Biotechnology Chemistry; Cells; Clinical Medicine; Dynamics; Drug design and drug discovery Energy metabolism; Equilibrium-NMR studying Folding; Flexibility; Flow-NMR Graphics Hydrogen-exchange; HPLC-NMR Interactions; In Vivo Measurements; Imaging J-coupling; NMR Applications —— A-Z THNMR YAN Kinetics Lipids, Ligands Binding Membrane proteins; Medicine; Micro-imaging; Material Science Na23-NMR Oil detection Protein structures; Partially structured proteins; Pharmacokinetics; Physics; Physiology Quantum computation Recognition; RNA structures NMR Applications —— A-Z Structural Biology; Solid-state NMR Tertiary structure; Toxicology Ultrafast kinetics Visualization Water Xe-NMR Yielding Zoology THNMR YAN Big Science NMR THNMR YAN Numbers of NMR research groups newly established NMR centers wide applications automation a young emerging field of research About this course—— What will be covered? Introduction to the principles of NMR Theory required for the understanding of important experiments A selection of the most widely-used 2D NMR techniques Interpretation of these spectra Applications of NMR in Biological Science THNMR YAN and what not? quantum mechanical treatment of NMR (although some equations will occur!!!) solid state NMR, MRI techniques working with NMR data bases empirical correlations for chemical shifts (increment systems) THNMR YAN 相关课程 生物系课程 生物物理 生物物理前沿 医学物理 Advance NMR Spectroscopy (NMR Lab. 内部培训) 化学系课程 THNMR YAN 有机化合物结构鉴定与有机波谱学 分析化学 What is required? knowledge of 1D NMR, J coupling patterns, chemical shift etc., e.g., Biophysics, Analytical chemistry regular (!) attention of the course, since most "individual sections" require an understanding of the previous ones. "re-reading" (and "re-thinking"!) of the material on a regular basis, and working out your own solutions to the problems given in the course – to make sure that you have really grasped the concepts and developed a working knowledge! THNMR YAN 课程要求 THNMR YAN 掌握核磁共振技术的基本原理 熟悉核磁共振测量需要的样品要求 掌握核磁共振基本参数的含义,能够进行1D NMR谱的解析 熟悉2D NMR谱的含义和获得的信息和解析方 法 了解蛋白质结构计算的步骤 了解NMR在生命科学中的主要应用 Semina 课程设置 周 次 第 2 周 第 3 周 第 4 周 第 5 周 THNMR YAN 日 期 3月 7日 3 月 14 日 3 月 21 日 3 月 28 日 内 容 绪论 第一节 核磁共振基础(1) 学 时 1 2 第一节 核磁共振基础(2) 第二节 核磁共振一维谱(1)——1D 1H NMR 第二节 核磁共振一维谱(2)——1D 13C NMR 等 第三节 核磁共振二维谱(1)——基础 第三节 核磁共振二维谱(2)——常用二维谱 第四节 由 NMR 谱图进行蛋白质溶液结构计算介绍 第五节 NMR 在生物科学中的应用介绍(或 Seminar) 典型习题讲解和讨论/答疑 1 1 1 1 1 1 2 1 Seminar专题 Equilibrium NMR studies of unfolded and partially folded proteins Kinetic studies of protein folding using NMR spectroscopy Hydrogen Exchange in proteins using NMR Nucleic acids structure X-ray crystallography and NMR Nucleic acids structure NMR structures of large proteins and protein complexes Protein-DNA interactions from NMR In vivo NMR studies structure-based drug design from NMR Protein dynamics from NMR NMR and membrane proteins Paramagnetic NMR THNMR YAN Seminar专题要求 从所列题目中选择或者自选,自选的要与教师商量 题目在第3周(3月14日)课上交给老师 主要文献应在1997年以后 至少采用一篇综述性文献 2人一组,每组报告时间7分钟,讨论5分钟 提前3天交提纲 需要用多媒体的提前1天拷贝一下文件 THNMR YAN 参考书目 宁永成.《有机化合物结构鉴定与有机波谱学》,清华大学出 版社,第一,第二版 夏佑林.《生物大分子多维核磁共振》,中国科技大学出版社 Wüthrich K. NMR of Proteins and Nucleic Acids. New York: John Wiley and Sons, 1986 周海梦等,《生物物理》中核磁共振部分 ftp://glove.2y.net THNMR YAN Some literature recommendations Monographs - A.Abragam "The principles of Nuclear Magnetism", Oxford University Press, 1978 (6. Auflage),ISBN 0-198-51236-9. (physics, very gut & very difficult to understand, the "old testament" of NMR) - R. R. Ernst, G. Bodenhausen, A. Wokaun "Principles of NMR in One and Two Dimensions", Oxford Science Publ. 1987, ISBN 0-198-55647-0. (physical chemistry, very exact & very difficult, the "new testament") - O. W. Sørensen, G. W. Eich, M. H. Levitt, G. Bodenhausen, R. R. Ernst, Progr. NMR Spectrosc. 16, 163-192 (1983). (the original article about product operators, but very readable! – if you skip some paragraphs) - R. K. Harris "Nuclear Magnetic Resonance Spectroscopy, A Physicochemical View", Longman Scientific & Technical 1986, ISBN 0-582-44653-8. (easily readable introduction to basic concepts, no modern techniques) THNMR YAN - J. N. S. Evans "Biomolecular NMR Spectroscopy", Oxford University Press 1995, ISBN 0198-54766-8 (QP519.9.N83E94 1995). (stress on biomolecular NMR, incl. proteins & nucleic acids, but also including a compact, yet concise introduction, nice book, reasonably priced) - H. Kessler, M. Gehrke, C. Griesinger, Angew. Chem. Int. Edn. Engl. 1988, 27, 490-536. ( good review on all 2D techniques, incl. product operator explanation, still up to date) - W. R. Croasmun, W. M. K. Carlson, ed. "Two-Dimensional NMR Spectroscopy; Applications for Chemists and Biochemists", VCH 1994, ISBN 1-56081-664-3 (QD/96/N8/T87/1987). (mixture of introductory and application chapters, on heteronuclear spectroscopy etc., expensive) - D. Shaw, "Fourier Transform NMR Spectroscopy", Elsevier Scientific Publishing Co., New York, 1976 (Res. QC/762/S45/2/1984). (good on principle and features of FT, otherwise outdated) - J. K. M. Sanders, B. K. Hunter, "Modern NMR Spectroscopy, A Guide for Chemists", Oxford University Press, 2nd ed. 1993 (QD/96/N8/S25). (no product operator description, but very good description of applications for 2D techniques,incl. example spectra). - J. Cavanagh, W.J. Fairbrother, A. G> Palmer III, N. J. Skelton, "Protein NMR Spectroscopy, Principles and Practice", Academic Press, San Diego 1996, ISBN 0-12-164490-1 (QP551.P69726 1995) (Lots of theory, quantum-mechanics & product operators, FT, relaxation measurements, despitetitle large section on 2D methods) THNMR YAN Journals THNMR YAN Magnetic Resonance Journals General THNMR YAN •Journal of Magnetic Resonance (Academic Press) Specialized •J. Biomolecular NMR, Ed. K. Wuthrich, (published by Kluwer Academic Publishers). •Solid State Nuclear Magnetic Resonance (published by Elsevier Science ) •Journal of Magnetic Resonance Imaging •Magnetic Resonance in Medicine •Magnetic Resonance Imaging (Elsevier) •Magnetic Resonance in Chemistry (John Wiley & Sons) •Magnetic Properties and Magnetic Resonance •NMR in Biomedicine (John Wiley & Sons) •Quarterly of Magnetic Resonance in Biology and Medicine (Mediamix) Educational Concepts in Magnetic Resonance Applied and Review •Annual Reports on NMR Spectroscopy (Academic Press) •Applied Magnetic Resonance (Springer) •Progress in Nuclear Magnetic Resonance Spectroscopy (published by Elsevier Science ) •Bulletin of Magnetic Resonance (Journal of the International Society of Magnetic Resonance) •Magnetic Resonance Materials in Physics, Biology and Medicine •Magnetic Resonance Review (Gordon & Breach Publishers) •NMR: Basic Principles and Progress. NMR: Grundlagen und Fortschritte (Springer-Verlag) Welcome to the exiting field of Be patient! The system is coming up…… THNMR YAN