Computational Methods for Protein Structure Prediction and Fold Recognition... 1 I. Cymerman, M. Feder, M. PawŁowski, M.A. Kurowski, J.M.

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1 Contents Computational Methods for Protein Structure Prediction and Fold Recognition I. Cymerman, M. Feder, M. PawŁowski, M.A. Kurowski, J.M. Bujnicki 1 Primary Structure Analysis Database Searches Protein Domain Identification Prediction of Disordered Regions Secondary Structure Prediction Helices and Strands and Otherwise Transmembrane Helices Protein Fold Recognition Predicting All-in-One-Go Pitfalls of Fold Recognition References Meta Approaches to Protein Structure Prediction J.M. Bujnicki, D. Fischer 1 Introduction The Utility of Servers as Standard Tools for Protein Structure Prediction Consensus Meta-Predictors : Is the Whole Greater Than the Sum of the Parts? Automated Meta-Predictors Hybrid Methods: Going Beyond the Simple Selection of Models Future Prospects References

2 VIII Contents From Molecular Modeling to Drug Design M. Cohen-Gonsaud, V. Catherinot, G. Labesse, D. Douguet 1 Introduction General Context Comparative Modeling Drug Design and Screening Comparative Modeling Sequence Gathering and Alignment Sequence Database Searches Multiple Sequence Alignments Structural Alignments Fold Recognition Structural Alignment Refinement Active Site Recognition A Biological Application Complete Model Achievement Global Structure Modeling Optimization of Side-Chain Conformation Insertions/Deletions Building Modeling Protein Quaternary Structures Energy Minimization and Molecular Dynamics Model Validation Theoretical Model Validation Ligand-Based Model Selection Experimental Evaluation of Models Current Limitations Model-Based Drug Design Comparative Drug Design Docking Methodologies Knowledge-Based Potentials Regression-Based (or Empirical) Methods Physics-Based Methods Flexible Models Fragment-Based Drug Design Virtual Screening Using Models Docking Onto Medium Resolution Models Docking Onto High-Resolution Models Pharmacogenomic Applications A Challenging Application: the GPCRs Family-Wide Docking Side Effect Predictions Drug Metabolization Predictions Conclusions References

3 Contents Structure Determination of Macromolecular Complexes by Experiment and Computation F. Alber, N. Eswar, A. Sali 1 Introduction Hybrid Approaches to Determination of Assembly Structures Modeling the Low-Resolution Structures of Assemblies Representation of Molecular Assemblies Scoring Function Consisting of Individual Spatial Restraints Optimization of the Scoring Function Analysis of the Models Comparative Modeling for Structure Determination of Macromolecular Complexes Automated Comparative Protein Structure Modeling Accuracy of Comparative Models Prediction of Model Accuracy Docking of Comparative Models into Low-Resolution Cryo-EM Maps Example 1: A Partial Molecular Model of the 80S Ribosome from Saccharomyces cerevisiae Example 2: A Molecular Model of the E. coli 70S Ribosome Conclusions References IX Modeling Protein Folding Pathways C. Bystroff, Y. Shao 1 Introduction: Darwin Versus Boltzmann Protein Folding Pathway History Knowledge-Based Models for Folding Pathways I-sites: A Library of Folding Initiation Site Motifs HMMSTR: A Hidden Markov Model for Grammatical Structure ROSETTA: Folding Simulations Using a Fragment Library Results of Fully Automated I-SITES/ROSETTA Simulations Summary Topologically Correct Large Fragment Predictions Are Found Good Local Structure Correlates Weakly with Good Tertiary Structure

4 X Contents Average Contact Order Is Too Low How Could Automated ROSETTA Be Improved? HMMSTR-CM: Folding Pathways Using Contact Maps A Knowledge-Based Potential for Motif Motif Interactions Fold Recognition Using Contact Potential Maps Consensus and Composite Contact Map Predictions Ab Initio Rule-Based Pathway Predictions Selected Results of HMMSTR-CM Blind Structure Predictions A Prediction Using Templates and a Pathway A Prediction Using Several Templates Correct Prediction Using Only the Folding Pathway False Prediction Using the Folding Pathway. What Went Wrong? Future Directions for HMMTR-CM Conclusions References Structural Bioinformatics and NMR Structure Determination J.P. Linge, M. Nilges 1 Introduction: NMR and Structural Bioinformatics Algorithms for NMR Structure Calculation Distance Geometry and Data Consistency Nonlinear Optimization Sampling Conformational Space Modelling Structures with Limited Data Sets Internal Dynamics and NMR Structure Determination Calculating NMR Parameters from Molecular Dynamics Simulations Inferring Dynamics from NMR Data Structure Validation Structural Genomics by NMR Automated Assignment and Data Analysis Collaborative Computing Project for NMR (CCPN) SPINS Databanks and Databases BioMagResBank and PDB/RCSB Conclusions References

5 Contents Bioinformatics-Guided Identification and Experimental Characterization of Novel RNA Methyltransferases J.M. Bujnicki, L. Droogmans, H. Grosjean, S.K. Purushothaman, B. Lapeyre 1 Introduction Diversity of Methylated Nucleosides in RNA RNA Methyltransferases Structural Biology of RNA MTases and Their Relatives Traditional and Novel Approaches to Identification of New RNA-Modification Enzymes Bioinformatics: Terminology, Methodology, and Applications to RNA MTases The Top-Down Approach Top-Down Search for Novel RNA:m 5 C MTases in Yeast Top-Down Search for Bacterial and Archaeal m 1 A MTases Top-Down Search for Novel Yeast 2 -O-MTases The Bottom-Up Approach Bottom-Up Search for New Yeast RNA MTases Conclusions References XI Finding Missing trna Modification Genes: A Comparative Genomics Goldmine V. de Crécy-Lagard 1 Missing trna Modification Genes trna Modifications Compilation of the Missing trna Modification Genes Comparative Genomics: an Emerging Tool to Identify Missing Genes Finding Genes for Simple trna Modifications Paralog- and Ortholog-Based Identifications Comparative Genomics-Based Identifications Finding Complex Modification Pathway Genes Finding Missing Steps in Known Pathways Finding Uncharacterized Pathway Genes Identification of the preq Biosynthesis Pathway Genes Hunting for the Wyeosine Biosynthesis Genes Conclusions References

6 XII Contents Evolution and Function of Processosome, the Complex That Assembles Ribosomes in Eukaryotes: Clues from Comparative Sequence Analysis A. Mushegian 1 Introduction Sequence Analysis of the Processosome Components Intrinsic Features Evolutionarily Conserved Sequence Domains Kre33p, or Possibly AtAc: Protein with Multiple Predicted Activities Imp4/Ssf1/Rpf1/Brx1/Peter Pan Family of Proteins Diverse RNA-Binding Domains and Limited Repertoire of Globular Protein Interaction Modules Phyletic Patterns Concluding Remarks References Bioinformatics-Guided Experimental Characterization of Mismatch-Repair Enzymes and Their Relatives P. Friedhoff 1 Introduction Sau3AI and Related Restriction Endonucleases DNA Mismatch Repair Nicking Endonuclease MutH Sau3AI Similar Folds for N- and C-Terminal Domains Fold Recognition for the C-terminal of Sau3AI Biochemical and Biophysical Analysis Evidence for a Pseudotetramer That Induces DNA Looping Identification of the Methylation Sensor of MutH Evolutionary Trace Analysis Superposition of MutH with REases in Complexes with DNA Mutational Analysis of MutH Conclusions References

7 Contents XIII Predicting Functional Residues in DNA Glycosylases by Analysis of Structure and Conservation D.O. Zharkov 1 Introduction Generating Predictions: Sequence Selection and Analysis Testing the Predictions: Mutational Analysis of Residues Defining Substrate Specificity in Formamidopyrimidine-DNA Glycosylase Refining the Predictions: Analysis of Substrate Specificity in the Endonuclease III Family References Subject Index

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