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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.

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Presentation on theme: "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."— Presentation transcript:

1 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…)

2 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

3 Chemical basis: Bonding Covalent Bonds: sharing of e - –One pair shared = single bondC C –Two pairs = double bondC C –Three pairs = triple bondC C Electronegativity (EN) is the ability of an atom to attract electrons to itself –C = 2.5N = 3.0 O = 3.5 H = 2.1 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

4 Chemical basis: Bonding Noncovalent Bonds: attractive forces between atoms of opposite charge –Ionic: fully chargedNa+ Cl- Strength dependent on environment (salt crystal vs aqueous) –Hydrogen: partial charge (polar molecules)

5 Noncovalent bonding Noncovalent Bonds: continued… –Van der Waals: transient dipole interactions –Hydrophobic: water fearing –Hydrophilic: water loving

6 Robot Lizards Exploit Van der Waals contacts Based on the Gecko Adhesion depends on close contact between surfaces “StickyBot” Video link

7 H2O Can form 4 hydrogen bonds –High energy barrier to liquid --> gas phase transition Highly polarized –Asymmetric structure - both H atoms on one side –Can dissolve many compounds

8 H2O Can dissolve many compounds –Acids: can release H+ –Bases: can accept H+ pH = - log [H+] Pure H2O pH = 7, [H+] = [OH - ] = M Why are reactions so pH sensitive? –Amino acid functional groups can change state based on pH

9 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.

10 Chirality and Stereoisomerism 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

11 Classes of molecules Miscellaneous co-factors –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

12 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

13 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

14 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

15 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

16 Monomers and polymers

17 Classes of molecules Macromolecules –Carbohydrates ( CH2O )n At n ≥ 5 self-reaction to form rings –C5 = ribose monomer –C6 = glucose monomer

18 Classes of molecules Macromolecules –“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

19 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

20 Classes of molecules Macromolecules –Nucleic Acids Nucleotide monomers (rNTPs, dNTPs) Storage and transmission of genetic information –Phosphate + 5C ribose sugar + nitrogenous base RNADNA H

21 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. Classes of molecules

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24 DNA is a useful reference-frame for sizes

25 Classes of molecules Macromolecules –Proteins Amino acid monomers Peptide bond formation N-terminus versus C-terminus Backbone is common, side chains (R) differ

26 Classes of molecules Macromolecules –Proteins Backbone is common, side chains differ –4 categories of amino acid side chains »Polar chargedD, E, K, R, H »Polar uncharged »Nonpolar »Unique

27 Classes of molecules Macromolecules –Proteins Backbone is common, side chains differ –4 categories of amino acid side chains »Polar chargedD, E, K, R, H »Polar unchargedS, T, Q, N, Y »Nonpolar »Unique Post-translational modifications: Phosphorylation of –OH groups

28 Classes of molecules Macromolecules –Proteins Backbone is common, side chains differ –4 categories of amino acid side chains »Polar chargedD, E, K, R, H »Polar unchargedS, T, Q, N, Y »NonpolarA, V, L, I, M, F, W »Unique

29 Classes of molecules Macromolecules –Proteins Backbone is common, side chains differ –4 categories of amino acid side chains »Polar chargedD, E, K, R, H »Polar unchargedS, T, Q, N, Y »NonpolarA, V, L, I, M, F, W »UniqueG, C, P

30 Hydrophobic and hydrophilic amino acid residues in the protein cytochrome c

31 Levels of protein structure Primary –Sequence of the polypeptide chain H 3 N -MQWERTYIHAHAPKLCVN- COOH H 3 N- Met Gln Trp Glu Arg Thr Tyr Ile… H 3 N -Methionine Glutamine Tryptophan…

32 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

33 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

34 Protein domains can be modular Protein Domains –Domains occur when proteins are composed of two or more distinct regions. –Each domain is a functional region

35 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…)

36 Levels of protein structure Quaternary –Interactions between 2 or more distinct polypeptide chains

37 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.

38 Disease Sickle-Cell Anemia (SCA) Painful Life-threatening periods of crisis e.g. vaso-occlusive crisis block blood flow in capillaries

39 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 E6  V

40 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

41 Two alternate pathways for protein folding

42 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)

43 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

44 Protein folding and Disease CJD (Mad Cow) & Alzheimers Disease –PrP C --> PrP Sc --> plaque –APP --> Ab42 --> plaque


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