Protein Secondary and Tertiary Structure Prediction in BCB 444/544 Fall 07 - Prof. Drena L, Lab Reports of Bioinformatics

Download Protein Secondary and Tertiary Structure Prediction in BCB 444/544 Fall 07 - Prof. Drena L and more Lab Reports Bioinformatics in PDF only on Docsity! #22 - Secondary & Tertiary Structure Prediction 10/12/07 BCB 444/544 Fall 07 Dobbs 1 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction BCB 444/544 Lecture 22  Secondary Structure Prediction Tertiary Structure Prediction #22_Oct10 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Mon Oct 8 - Lecture 20 Protein Secondary Structure Prediction • Chp 14 - pp 200 - 213 Wed Oct 10 - Lecture 21 Protein Tertiary Structure Prediction • Chp 15 - pp 214 - 230 Thurs Oct 11 & Fri Oct 12 - Lab 7 & Lecture 22 Protein Tertiary Structure Prediction • Chp 15 - pp 214 - 230 Required Reading (before lecture) 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Assignments & Announcements ALL: HomeWork #3 √ Due: Mon Oct 8 by 5 PM • HW544: HW544Extra #1 √ Due: Task 1.1 - Mon Oct 1 by noon Due: Task 1.2 & Task 2 - Fri Oct 12 by 5 PM • 444 "Project-instead-of-Final" students should also submit: • HW544Extra #1 • √ Due: Task 1.1 - Mon Oct 8 by noon •Due: Task 1.2 - Fri Oct 12 by 5 PM <Task 2 NOT required for BCB444 students> 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction New Reading & Homework Assignment ALL: HomeWork #4 (posted online today) Due: Fri Oct 19 by 5 PM (one week from today) Read: Ginalski et al.(2005) Practical Lessons from Protein Structure Prediction, Nucleic Acids Res. 33:1874-91. http://nar.oxfordjournals.org/cgi/content/full/33/6/1874 (PDF posted on website) • Although somewhat dated, this paper provides a nice overview of protein structure prediction methods and evaluation of predicted structures. • Your assignment is to write a summary of this paper - for details see HW#4 posted online & sent by email on Fri Oct 12 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Seminars this Week - (yesterday) BCB List of URLs for Seminars related to Bioinformatics: http://www.bcb.iastate.edu/seminars/index.html • Oct 11 Thurs • Dr. Klaus Schulten (Univ of Illinois) - Baker Center Seminar The Computational Microscope 2:10 PM in E164 Lagomarcino http://www.bioinformatics.iastate.edu/seminars/abstracts/2007_2008/ Klaus_Schulten_Seminar.pdf • Dr. Dan Gusfield (UC Davis) - Computer Science Colloquium ReCombinatorics: Combinatorial Algorithms for Studying History of Recombination in Populations 3:30 PM in Howe Hall Auditorium http://www.cs.iastate.edu/~colloq/new/gusfield.shtml 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Seminars this Week - Fri (today) BCB List of URLs for Seminars related to Bioinformatics: http://www.bcb.iastate.edu/seminars/index.html • Oct 12 Fri • Dr. Edward Yu (Physics/BBMB, ISU) - BCB Faculty Seminar TBA: "Structural Biology" (see URL below) 2:10 PM in 102 Sci http://webdev.its.iastate.edu/webnews/data/site_gdcb_dept_seminars/30/webne wsfilefield_abstract/Dr.-Ed-Yu.pdf • Dr. Srinivas Aluru (ECprE, ISU) - GDCB Seminar Consensus Genetic Maps: A Graph Theoretic Approach 4:10 PM in 1414 MBB http://webdev.its.iastate.edu/webnews/data/site_gdcb_dept_seminars/35/web newsfilefield_abstract/Dr.-Srinivas-Aluru.pdf #22 - Secondary & Tertiary Structure Prediction 10/12/07 BCB 444/544 Fall 07 Dobbs 2 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Chp 12 - Protein Structure Basics SECTION V STRUCTURAL BIOINFORMATICS Xiong: Chp 12 Protein Structure Basics • Amino Acids • Peptide Bond Formation • Dihedral Angles • Hierarchy • Secondary Structures • Tertiary Structures • Determination of Protein 3-Dimensional Structure • Protein Structure DataBank (PDB) 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Experimental Determination of 3D Structure 2 Major Methods to obtain high-resolution structures 1. X-ray Crystallography (most PDB structures) 2. Nuclear Magnetic Resonance (NMR) Spectroscopy Note Advantages & Limitations of each method • (See your lecture notes & textbook) • For more info: http://en.wikipedia.org/wiki/Protein_structure 3.Other methods (usually lower resolution, at present): • Electron Paramagnetic Resonance (EPR - also called ESR, EMR) • Electron microscopy (EM) • Cryo-EM • Scanning Probe Microscopies (AFM - Atomic Force Microscopy) • http://www.uweb.engr.washington.edu/research/tutorials/SPM.pdf • Circular Dichroism (CD), several other spectroscopic methods 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction "Best" Resolution of Protein Structures • High-resolution methods • X-ray crystallography (< 1A°) • NMR (~1 - 2.5A°) • Lower-resolution methods • Cryo-EM (~10-15A°) • Theoretical Models? • Usually low resolution, at present, but • Highly variable - & a few ~crystal data Baker & Sali (2000)Pevsner Fig 9.36 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Chp 13 - Protein Structure Visualization, Comparison & Classification SECTION V STRUCTURAL BIOINFORMATICS Xiong: Chp 13 Protein Structure Visualization, Comparison & Classification • Protein Structural Visualization • Protein Structure Comparison - later • Protein Structure Classification 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Protein Structure Classification • SCOP = Structural Classification of Proteins Levels reflect both evolutionary and structural relationships http://scop.mrc-lmb.cam.ac.uk/scop • CATH = Classification by Class, Architecture,Topology & Homology http://cathwww.biochem.ucl.ac.uk/latest/ • DALI - (recently moved to EBI & reorganized) DALI Database (fold classification) http://ekhidna.biocenter.helsinki.fi/dali/start Each method has strengths & weaknesses…. 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Chp 14 - Secondary Structure Prediction SECTION V STRUCTURAL BIOINFORMATICS Xiong: Chp 14 Protein Secondary Structure Prediction • Secondary Structure Prediction for Globular Proteins • Secondary Structure Prediction for Transmembrane Proteins • Coiled-Coil Prediction #22 - Secondary & Tertiary Structure Prediction 10/12/07 BCB 444/544 Fall 07 Dobbs 5 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Chp 15 - Tertiary Structure Prediction SECTION V STRUCTURAL BIOINFORMATICS Xiong: Chp 15 Protein Tertiary Structure Prediction • Methods • Homology Modeling • Threading and Fold Recognition • Ab Initio Protein Structural Prediction • CASP 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Structural Genomics - Status & Goal ~ 20,000 "traditional" genes in human genome (recall, this is fewer than earlier estimate of 30,000) ~ 2,000 proteins in a typical cell > 4.9 million sequences in UniProt (Oct 2007) > 46,000 protein structures in the PDB (Oct 2007) Experimental determination of protein structure lags far behind sequence determination! Goal: Determine structures of "all" protein folds in nature, using combination of experimental structure determination methods (X-ray crystallography, NMR, mass spectrometry) & structure prediction 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Structural Genomics Projects TargetDB: database of structural genomics targets http://targetdb.pdb.org 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Protein Sequence & Structure: Analysis • Diamond STING Millennium - Many useful structure analysis tools, including Protein Dossier http://trantor.bioc.columbia.edu/SMS/ • SwissProt (UniProt) Protein knowledgebase http://us.expasy.org/sprot • InterPro Sequence analysis tools http://www.ebi.ac.uk/interpro 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Protein Structure Prediction or Protein Folding Problem "Major unsolved problem in molecular biology" In cells: spontaneous assisted by enzymes assisted by chaperones In vitro: many proteins can fold to their "native" states spontaneously & without assistance but, many do not! 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Deciphering the Protein Folding Code • Protein Structure Prediction or "Protein Folding" Problem Given the amino acid sequence of a protein, predict its 3-dimensional structure (fold) • "Inverse Folding" Problem Given a protein fold, identify every amino acid sequence that can adopt that 3-dimensional structure #22 - Secondary & Tertiary Structure Prediction 10/12/07 BCB 444/544 Fall 07 Dobbs 6 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Protein Structure Prediction Structure is largely determined by sequence BUT: • Similar sequences can assume different structures • Dissimilar sequences can assume similar structures • Many proteins are multi-functional 2 Major Protein Folding Problems: 1- Determination of folding pathway 2- Prediction of tertiary structure from sequence Both still largely unsolved problems 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Steps in Protein Folding 1-"Collapse"- driving force is burial of hydrophobic aa’s (fast - msecs) 2- Molten globule - helices & sheets form, but "loose" (slow - secs) 3- "Final" native folded state - compaction & rearrangement of some 2' structures Native state? - assumed to be lowest free energy - may be an ensemble of structures 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Protein Dynamics • Protein in native state is NOT static • Function of many proteins requires conformational changes, sometimes large, sometimes small • Globular proteins are inherently "unstable" (NOT evolved for maximum stability) • Energy difference between native and denatured state is very small (5-15 kcal/mol) (this is equivalent to ~ 2 H-bonds!) • Folding involves changes in both entropy & enthalpy 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction Difficulty of Tertiary Structure Prediction Folding or tertiary structure prediction problem can be formulated as a search for minimum energy conformation • Search space is defined by psi/phi angles of backbone and side-chain rotamers • Search space is enormous even for small proteins! • Number of local minima increases exponentially with number of residues Computationally it is an exceedingly difficult problem! 10/12/07BCB 444/544 F07 ISU Dobbs #22 - Secondary & Tertiary Structure Prediction From Thursday's Lab: • Homology Modeling - using SWISS-MODEL • http://swissmodel.expasy.org//SWISS-MODEL.html • Threading - using 3-D JURY (BioinfoBank, a METAserver) • http://meta.bioinfo.pl/submit_wizard.pl • Be sure to take a look at CASP contest: • http://predictioncenter.gc.ucdavis.edu/ • CASP7 contest in 2006 • http://www.predictioncenter.org/casp7/Casp7.html