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Macromolecular Structure: Introduction
Andy Howard Biology 555, Fall 2018 21 August 2018
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Macromolecular Structure
This course is intended to familiarize you with the methods and the results associated with the structures of biological macromolecules. We will look at several methods at varying levels of detail We hope to leave you with an awareness of structural realities—this is not just a methods course 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
Who are we? I’m a protein crystallographer, so the extended period we spend talking about crystallography is from my own domain Tom Irving is a physiologist and biophysicist, and is adept at building teams to do excellent science using SAXS and other techniques Joseph Orgel is a fiber diffractionist and a world leader in connective tissue 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
How this course fits in To some degree this course is intended as the apex of the molecular biochemistry & biophysics graduate program But it’s also a valuable elective for students in biochemistry and cell & molecular biology It approaches biochemical issues without flinching at the rigor brought out through physics, particularly in terms of methods 08/21/2018 Macromolecular Structure: Introduction
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How does this course help you?
If you’re a cell biologist, molecular biologist, or biochemist, you’re eventually going to need macromolecular structural information This course will help you obtain that or at least read the literature with a critical eye It will enable you to compare methods and choose tools that are appropriate to the problem you’re trying to address 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
The Team Andrew Howard: course manager and macromolecular crystallography Tom Irving or Srinivas Chakravarthy: solution scattering Likely Guest lectures: Grant Bunker (XAFS), Jeff Wereszczynski (simulations), Joseph Orgel (fiber crystallography) 08/21/2018 Macromolecular Structure: Introduction
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Structure and function
The reason we care about macromolecular structure is that it clarifies function If we know the structure of a macromolecule (protein or nucleic acid), we can: Figure out how it does what it does if we already had an idea of its function Determine its function if we don’t already know it Once we recognize function, we can use it to deepen understanding or design drugs 08/21/2018 Macromolecular Structure: Introduction
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Schedule: generalities
Full schedule is on the Blackboard site We won’t make major adjustments in the schedule after the first week, although there will be minor shifts As of this moment it’s pretty vague, though 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
Schedule: specifics Today: Fundamentals of protein structure Thursday: Finish structure fundamentals, and then: biophysical mathematics then: scattering and diffraction see the Blackboard site for the rest 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
Grading This is a real graduate class, and we want the evaluation to be individualized 1/3 based on homework assignments that grow out of the lectures 1/3 based on a take-home final 1/3 based on three papers you’ll write You may work together on homework but what you hand in must be your own Final must be individual: cheating will not be tolerated 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
Goals & Objectives Recognize how the various methods work Recognize which methods provide the particular kinds of information we seek Know primary, secondary, tertiary, and quaternary structure elements in proteins and nucleic acids Recognize the significance of mobility and dynamics in macromolecular structure and function 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
What you need to know Complex numbers, Fourier transforms, statistics Protein structure elements Central dogma Role of solvent in macromolecules Remember: macromolecules aren’t static 08/21/2018 Macromolecular Structure: Introduction
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Lecture 1: General Principles of Macromolecular Structure
These lecture notes are a heavily modified form of what was originally a Tom Irving lecture Macromolecules include proteins, RNA, DNA, and polysaccharides What are some general rules governing macromolecular structure? 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
What's a molecule? Stoichiometry (chemical formula) Bonds and symmetry Not easily dissociated Molecular identity depends on geometry, not just its chemical formula Aldohexose sugars C6H12O6 : 16 = 24 possible stereoisomers 08/21/2018 Macromolecular Structure: Introduction
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What’s a macromolecule?
A large molecule Macromolecules are polymers of > ~50 residues "Residue" = amino acid, nucleic acid base, sugar moiety i.e. monomers Arbitrary distinction: Fewer than residues is an oligomer More than residues is a polymer 08/21/2018 Macromolecular Structure: Introduction
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Size & complexity of biopolymers
Class Example Size Molecular Weight Subunit type # of subunits Oligomer Actinomycin D 20Å sphere Atoms /residues 102 / 10 Small proteins Chymotrypsin 40Å sphere amino acid residues Nucleic acids mRNA 100Å rod nucleo-tides 08/21/2018 Macromolecular Structure: Introduction
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Size & Complexity, concluded
Class Example Size Molecular Weight Subunit type # of subunits Large proteins ATCase 70Å sphere Subunits / chains 10-100 Small assemblies Ribosome 200Å sphere Large assemblies Membranes, viruses 1000Å sphere Com-ponents Intact DNA E.coli DNA 0.1cm rod Genes 08/21/2018 Macromolecular Structure: Introduction
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Hierarchy of Structural Levels
Primary structure Linear sequence of monomers in macromolecule Secondary structure Local 3-D Structure Defined primarily by main-chain H-bonds Tertiary Structure Global 3-D structure -”Fold” Quaternary structure Spatial arrangement of multiple polymeric chains. 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
4 Levels Secondary structures defined by main-chain hydrogen bonds and (possibly) disulfides Tertiary and quaternary structures involve many H-bonds, van der Waals contacts Image courtesy Wikimedia 08/21/2018 Macromolecular Structure: Introduction
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Structure vs Structural Models
Cannot generally "see" a molecule Biophysical techniques allow construction of "models" of molecular structure Models may be very schematic Block diagrams of various domains Or detailed atomic "structures" from X-ray crystallography or 3-D NMR A list of atomic coordinates Should not be confused with "real thing" 08/21/2018 Macromolecular Structure: Introduction
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Structural models, continued
So we need to be conscious of the deficiencies in our models We also need to recognize that our visual representation of that model can be deficient Often what we leave out of our visual representation is as important as what we include! 08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
08/21/2018 Macromolecular Structure: Introduction
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Macromolecular Structure: Introduction
The "Folding Problem" Primary structure contains all necessary information to determine tertiary structure How does it get there? How can we predict tertiary structure from primary structure? Intense area of research 08/21/2018 Macromolecular Structure: Introduction
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A subtle definitional issue
The folding problem as defined on the previous slide is the traditional one An alternative is to emphasize the dynamics of protein folding: How does the unique 3-D structure arise in the cell? Probably it isn’t properly folded the moment it emerges from the ribosome Presumably there are forces that direct the protein into its final conformation So make sure your listeners know which definition you’re using! 08/21/2018 Macromolecular Structure: Introduction
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Prominent secondary structures
helix antiparallel sheet polyproline helix 08/21/2018 Macromolecular Structure: Introduction
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