Fundamentals of Molecular Structural Biology

Fundamentals of Molecular Structural Biology reviews the mathematical and physical foundations of molecular structural biology. Based on these fundamental concepts, it then describes molecular structure and explains basic genetic mechanisms. Given the increasingly interdisciplinary nature of research, early career researchers and those shifting into an adjacent field often require a "fundamentals" book to get them up-to-speed on the foundations of a particular field. This book fills that niche. Provides a current and easily digestible resource on molecular structural biology, discussing both foundations and the latest advances Addresses critical issues surrounding macromolecular structures, such as structure-based drug discovery, single-particle analysis, computational molecular biology/molecular dynamic simulation, cell signaling and immune response, macromolecular assemblies, and systems biology Presents discussions that ultimately lead the reader toward a more detailed understanding of the basis and origin of disease Cover Fundamentals of Molecular Structural Biology Copyright Dedication About the Author Preface Acknowledgments 1 Introduction-A historical perspective Biology begins as natural history Nature of matter Microscope reveals internal structure of living organisms Cell theory Theory of natural selection and laws of heredity Gene and genetics Nature of ``physical objects ́ ́ in the cell DNA as the genetic material Biology turns molecular-natural science becomes unified Deeper into the structure of matter Molecular biology endowed with structures Structural complex(ity) disentangled Molecular structural biology confronts human disease From gene to genome In lieu of a conclusion References and Further Reading 2 Mathematical tools Measurements: Standards and units Algebraic functions Trigonometric functions Exponential and logarithm Complex numbers Vector Matrix Calculus Differentiation Integration Multivariate function Applications Vector operators Series and transform Sample questions References and further reading 3 Physical basis of chemistry Classical mechanics Matter and motion Fundamental forces of nature Newtons laws Circular motion and angular momentum Work and energy Oscillatory systems Wave motion Mechanical waves Electromagnetic wave Interference of light waves Kinetic theory of gases Thermodynamics Quantum physics Light as photons Matter as waves Schrdinger equation Barrier tunneling by free electron Bound electron-Hydrogen atom Some elements of statistics Microscopic versus macroscopic Normal distribution Boltzmann distribution Sample questions References and further reading 4 Chemical basis of biology From atoms to molecules Electron configuration of atoms Atomic interactions-Chemical bonds Electron sharing principles-Electronegativity Polarity of bond-Molecular dipole Bonding theories Valence bond theory Molecular orbital theory Noncovalent interactions Ion-ion interactions Ion-dipole interactions Ion-induced dipole interactions Van der Waals interactions-Leonard-Jones potential Dipole-dipole Dipole-induced dipole Induced dipole-induced dipole-London forces Leonard-Jones potential Hydrogen bond and water structure Chemical thermodynamics-Free energy Entropy and hydrophobicity Chemical kinetics Rate law-Arrhenius equation Collison theory Transition state theory Quantum tunneling Nucleophilic-electrophilic-SN2 reaction Sample questions References and further reading 5 Biomacromolecules Nucleic acids Nucleotides The DNA double helix Thermodynamics of double helix formation Major and minor grooves Multiple conformation of the double helix DNA superhelicity Proteins Amino acids Peptide bond Secondary structures Supersecondary and tertiary structures Motifs Folds Domains Quaternary structure Protein flexibility and dynamics Carbohydrates Sample questions References and further reading 6 Structure analysis and visualization X-ray crystallography Scattering of X-rays by atoms Diffraction from a crystal The phase problem Direct methods Molecular replacement (MR) Isomorphous replacement Multiwavelength anomalous dispersion Temperature factor Refinement Nuclear magnetic resonance (NMR) Basic principles Chemical shift J-Coupling Nuclear overhauser effect (NOE) Structure computation Cryo-electron microscopy Physical principles Problem of imaging biomolecules Three-dimensional electron microscopy Cryo-electron tomography Electron crystallography Single-particle analysis Representation of structures Structural data Line representation Spheres-CPK representation Ribbon representation DNA Surface representation Surface hydrophobicity and charge Volume representation Occupancy Temperature factor Sample questions References and further reading 7 Protein folding The protein folding problem Physical forces in protein folding Protein energy landscape Folding in cellular environment Some model chaperones Trigger factor Spy Hsp60 Chaperonin containing TCP1 Sample questions References and further reading 8 DNA synthesis: Replication Thermodynamics of DNA synthesis Mechanism of DNA synthesis Structural and functional diversity Common architecture of DNA polymerases Primer:template DNA-binding to enzyme Formation of E:p/t:dNTP ternary complex Phosphoryl transfer reaction Cellular context Initiation of bacterial DNA replication Melting of the DNA-Replicator and initiator Unwinding of the DNA-Helicase and helicase loader Priming DNA synthesis-Primase and SSB Bacterial replicase The polymerase The processivity clamp The clamp loader Proofreading Disentanglement of replication products A glimpse of eukaryotic replication Initiation of replication Multiple polymerases at work Sample questions References and further reading 9 Transcription Basic requirements for transcription Bacterial transcription Bacterial RNA polymerase Promoter Initiation: Holoenzyme-DNA interactions Promoter recognition and binding Open promoter complex Initiation Promoter escape Elongation Nucleotide addition cycle RNAP fidelity Termination Intrinsic Rho-dependent Eukaryotic transcription RNA polymerase II Promoter General transcription factors TFIID TFIIA TFIIB TFIIF TFIIE TFIIH Transcriptional regulation Prokaryotic regulation The lac operon Negative control (repression) Positive control (activation) Eukaryotic regulation Mediator Gene regulatory proteins Gcn4 p53 Sample questions References and further reading 10 RNA processing RNA Pol II CTD 5-End capping 3-End polyadenylation CFI CPSF CstF CFII RNA splicing Chemistry Spliceosome dynamics RNA editing Site-specific deamination Guide RNA-directed editing Sample questions References and further reading 11 Translation Transfer of genetic information-From mRNA to protein Protein synthesis Messenger RNA-Genetic code Transfer RNA-Means of information transfer Aminoacyl-tRNA synthetase-Activation of tRNA Mechanism of aminoacylation Editing by aminoacyl-tRNA synthetase The ribosome-Multicompartmental reaction vessel Initiation of translation Prokaryotic Eukaryotic Translation elongation Decoding Peptidyl transfer Translocation Translation termination Sample questions References and further reading 12 DNA damage and repair Structural chemistry of DNA damage Spontaneous reactions Chemical damage Alkylation Aromatic amines Oxidative damage Radiation damage Mismatch repair Direct reversal of damage Base excision repair Nucleotide excision repair Translesion synthesis Sample questions References and further reading 13 Recombination Homologous recombination Initiation of recombination: Resection and recombinase loading Bacteria Eukaryotes Homologous DNA pairing and strand exchange Bacteria Eukaryotes Branch migration and Holliday junction resolution Bacteria Eukaryotes DNA rearrangements Conservative site-specific recombination Transpositional recombination Sample questions References and further reading 14 Membrane structure and function Composition of the membrane Membrane structure Membrane dynamics Transport across membranes Passive transport Ligand-gated channel Voltage-gated channel Carrier protein-facilitated diffusion Active transport Transport in vesicles Endocytosis Exocytosis Signal transduction Sample questions References and further reading 15 Fundamentals of structural genomics Genome sequencing Sanger-automated sequencing Next-generation sequencing Genome annotation Structural genomics/proteomics Experimental structure determination Computational structure prediction Comparative modeling Threading Fragment-based recombination Physics-based ab initio modeling Function prediction Structural genomics initiatives Sample questions References and further reading 16 Cell signaling and systems biology Cell signaling Pathway as signal amplifier Signaling by phosphorylation MAPK pathway ERK2 MEK MKP3 Structural basis of immune response Structural systems biology Sample questions References and further reading 17 Macromolecular assemblies Molecular self-assembly Principles of self-assembly Biomacromolecular complexes Viral capsids Ribosome assembly Single-particle cryo-electron microscopy Sample questions References and further reading 18 Computational molecular biology Modeling and simulation Molecular dynamics Basic theory Simulation of a cellular process Drug design Hemoglobin and sickle cell disease Enzyme inhibitors as drugs HIV protease as drug target Targeting interaction networks Computational drug screening Sample questions References and further reading Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Fundamentals of molecular Structural Biology offers a comprehensive treatment of the subject, with an appropriate blend of mathematical, physical, and biological topics to provide a foundational understanding of the structural-functional aspects of biological macromolecules involved in the basic genetic mechanisms. A series of initial refresher chapters addressed the foundation of necessary mathematical and physical concepts. They are followed by sections that delve deeper into macromolecular structures, which are then utilized to explain the basic genetic mechanisms. Advanced issues surrounding macromolecular structures, namely, cell signaling and systems biology, macromolecular assemblies, and computational molecular biology, are also covered __Fundamentals of Molecular Structural Biology__ reviews the mathematical and physical foundations of molecular structural biology. Based on these fundamental concepts, it then describes molecular structure and explains basic genetic mechanisms. Given the increasingly interdisciplinary nature of research, early career researchers and those shifting into an adjacent field often require a "fundamentals" book to get them up-to-speed on the foundations of a particular field. This book fills that niche.