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Intro to Cell & Molecular Biology
How do we study cell biology? Reductionist view Cells as tiny complex machines Sum of parts = whole Your goal: be able to explain the roles various molecular parts play in cell biological processes With the same clarity as with macroscopic items (bicycles, stoves, trains, etc…)
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Intro to Cell & Molecular Biology
How do we study cell biology? Parsimony the simplest explanation for all relevant data is preferred over more complex explanations The most parsimonious answer is not necessarily perfectly correct More data could make us revise it
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Chemical basis: Bonding
Covalent Bonds: sharing of e- One pair shared = single bond C C Two pairs = double bond C C Three pairs = triple bond C C Electronegativity (EN) is the ability of an atom to attract electrons to itself C = 2.5 N = O = H = S = 2.6 Sharing is unequal between different atoms in a molecule Polar molecules have significant EN differences H2O, CH3COOH Nonpolar molecules have little EN differences CH3(CH2)nCH3 Amphipathic molecules have different EN characteristics at different positions CH3(CH2)nCOOH
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Chemical basis: Bonding
Noncovalent Bonds: attractive forces between atoms of opposite charge Ionic: fully charged Na+ Cl- Strength dependent on environment (salt crystal vs aqueous) Hydrogen: partial charge (polar molecules)
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Noncovalent bonding Noncovalent Bonds: continued…
Van der Waals: transient dipole interactions Hydrophobic: water fearing Hydrophilic: water loving
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Robot Lizards Exploit Van der Waals contacts
Based on the Gecko Adhesion depends on close contact between surfaces “StickyBot” Video link
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H2O Can form 4 hydrogen bonds Highly polarized
High energy barrier to liquid --> gas phase transition Highly polarized Asymmetric structure - both H atoms on one side Can dissolve many compounds
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H2O Can dissolve many compounds Why are reactions so pH sensitive?
Acids: can release H+ Bases: can accept H+ pH = - log [H+] Pure H2O pH = 7 , [H+] = [OH-] = 10-7 M Why are reactions so pH sensitive? Amino acid functional groups can change state based on pH
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Carbon Central to the chemistry of life.
Can form four covalent bonds, with itself or other atoms. Carbon-containing molecules produced by living organisms are called biochemicals.
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Chirality and Stereoisomerism
Asymmetric carbons bond to four different groups. Two mirror-image configurations: Enantiomers, (aka) Stereoisomers Can be either D- or L-isomers Natural amino acids = almost all L-isomers Natural carbohydrates = almost all D-isomers
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Classes of molecules Miscellaneous co-factors Metabolic intermediates
Vitamins, ATP, NADPH, etc Metabolic intermediates Glycolysis, TCA cycle, etc Monomers Amino acids rNTPs = A, G, C, U dNTPs = A, G, C, T Sugars Macromolecules
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Classes of molecules Macromolecules Lipids
Fats = glycerol esterified with 3 fatty acids Saturated, unsaturated, cis, trans Phospholipids = glycerol + 2 fatty acids + 1 phosphate Steroids = cholesterol and derivatives
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Classes of molecules Macromolecules Lipids
Fats = glycerol esterified with 3 fatty acids Saturated, unsaturated, cis, trans Phospholipids = glycerol + 2 fatty acids + 1 phosphate Steroids = cholesterol and derivatives
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Classes of molecules Macromolecules Lipids
Fats = glycerol esterified with 3 fatty acids Saturated, unsaturated, cis, trans Phospholipids = glycerol + 2 fatty acids + 1 phosphate Steroids = cholesterol and derivatives
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Classes of molecules Macromolecules Lipids
Fats = glycerol esterified with 3 fatty acids Saturated, unsaturated, cis, trans Phospholipids = glycerol + 2 fatty acids + 1 phosphate Steroids = cholesterol and derivatives
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Monomers and polymers
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Classes of molecules Macromolecules Carbohydrates ( CH2O )n
At n ≥ 5 self-reaction to form rings C5 = ribose monomer C6 = glucose monomer
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Classes of molecules Macromolecules plastid “Nutritional” sugars:
Glycogen = branched alpha 1-4 linkage, dense granules in cell cytoplasm in animals Starch = helical and branched alpha 1-4 linkage, within membrane bound plastids in plants plastid
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Classes of molecules Macromolecules “Structural” sugars:
Cellulose = long and unbranched, beta 1-4 linkage, resist tensile (pulling) forces, plants Chitin = unbranched, N-acetylglucosamine, invertebrates Glycosaminoglycans = components of extracellular matrix for cartilage and bone, repeating (A-B)n structure
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Classes of molecules Macromolecules RNA DNA Nucleic Acids
Nucleotide monomers (rNTPs, dNTPs) Storage and transmission of genetic information Phosphate + 5C ribose sugar + nitrogenous base RNA DNA H
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Classes of molecules DNA is usually double stranded
RNA is usually single stranded RNA may fold back on itself to form complex 3D structures, as in ribosomes. RNA may have catalytic activity; such RNA enzymes are called ribozymes. Adenosine triphosphate (ATP) is a nucleotide that plays a key role in cellular metabolism Guanosine triphosphate (GTP) serves as a switch to turn on some proteins.
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DNA is a useful reference-frame for sizes
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Classes of molecules Macromolecules Proteins Amino acid monomers
Peptide bond formation N-terminus versus C-terminus Backbone is common, side chains (R) differ
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Classes of molecules Macromolecules Proteins
Backbone is common, side chains differ 4 categories of amino acid side chains Polar charged D, E, K, R, H Polar uncharged Nonpolar Unique
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Classes of molecules Macromolecules Proteins
Backbone is common, side chains differ 4 categories of amino acid side chains Polar charged D, E, K, R, H Polar uncharged S, T, Q, N, Y Nonpolar Unique Post-translational modifications: Phosphorylation of –OH groups
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Classes of molecules Macromolecules Proteins
Backbone is common, side chains differ 4 categories of amino acid side chains Polar charged D, E, K, R, H Polar uncharged S, T, Q, N, Y Nonpolar A, V, L, I, M, F, W Unique
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Classes of molecules Macromolecules Proteins
Backbone is common, side chains differ 4 categories of amino acid side chains Polar charged D, E, K, R, H Polar uncharged S, T, Q, N, Y Nonpolar A, V, L, I, M, F, W Unique G, C, P
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Hydrophobic and hydrophilic amino acid residues in the protein cytochrome c
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Levels of protein structure
Primary Sequence of the polypeptide chain H3N-MQWERTYIHAHAPKLCVN-COOH H3N-Met Gln Trp Glu Arg Thr Tyr Ile… H3N-Methionine Glutamine Tryptophan…
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Levels of protein structure
Secondary Alpha-helix (collagen) Beta-sheet (spider silk) Side-chain dependence to which form is adopted but stabilization comes from backbone - backbone hydrogen bonding interactions
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Levels of protein structure
Tertiary Side-chain dependent and mediated packing of the secondary elements Fibrous proteins = elongated, often structural roles Globular = compact, often enzymes
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Protein domains can be modular
Domains occur when proteins are composed of two or more distinct regions. Each domain is a functional region
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Protein structures can be dynamic
Dynamic Changes within Proteins May occur with protein activity. Conformational changes are non-random movements triggered by various events (e.g. binding, chemical mods…)
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Levels of protein structure
Quaternary Interactions between 2 or more distinct polypeptide chains
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Protein-Protein Interactions
Results from large-scale studies can be presented in the form of a network. A list of potential interactions can elucidate unknown processes.
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Disease Sickle-Cell Anemia (SCA) Painful
Life-threatening periods of crisis e.g. vaso-occlusive crisis block blood flow in capillaries
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Disease Sickle-Cell Anemia (SCA)
Hemoglobin is composed of four polypeptide chains Two alpha-globin subunits + two beta-globin subunits SCA is caused by a single amino acid substitution in beta-globin E6V
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Protein structure and folding
Anfinsen RNase A experiment Denature (unfold) protein in urea Observed loss of activity Dialyze the urea away Observed refolding Regain of activity Demonstrated structural information is inherent to protein sequence Follow a folding pathway Fold to the lowest energy state
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Two alternate pathways for protein folding
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Chaperones prevent mis-folding
Molecular Chaperones HSP70 during translation of nascent peptide Binds exposed hydrophobic regions Hydrolyzes ATP in a bind-release cycle Hartl, et al (2011)
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Chaperones prevent mis-folding
Molecular Chaperones HSP70 during translation of nascent peptide Binds exposed hydrophobic regions Hydrolyzes ATP in a bind-release cycle Chaperonins assist post-translation
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Protein folding and Disease
CJD (Mad Cow) & Alzheimers Disease PrPC --> PrPSc --> plaque APP --> Ab42 --> plaque
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