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Biomolecules: Protein structure and function 3 2 Life and Chemistry: Large Molecules Outline of today’s talk: • Macromolecules: Giant Polymers • Condensation and Hydrolysis Reactions • Proteins: Polymers of Amino Acids • Protein structure & function 3 3 Macromolecules: Giant Polymers • Macromolecules are giant polymers (poly = “many”; mer= “unit”). • Polymers are formed by covalent linkages of smaller units called monomers. • Molecules with molecular weights greater than 1,000 daltons (atomic mass units) are usually classified as macromolecules. Figure 3.3 Condensation and Hydrolysis of Polymers (Part 1) • Macromolecules are made from smaller monomers by means of a condensation or dehydration reaction in which an OH from one monomer is linked to an H from another monomer. • Energy must be added to make a polymer. 3 5 Condensation and Hydrolysis Reactions The reverse reaction, in which polymers are broken back into monomers, is a called a hydrolysis reaction. 3 6 The Building Blocks of Organisms 26% 15% 7% Water 70% 2% 2% 2% 3 7 Macromolecules: Giant Polymers • These macromolecules are made the same way in all living things, and are present in all organisms in roughly the same proportions. • An advantage of this biochemical unity is that organisms acquire needed biochemicals by eating other organisms. 3 8 Macromolecules: Giant Polymers • The functions of macromolecules are related to their shape and the chemical properties of their monomers. • Some of the roles of macromolecules include: Energy storage Carbohydrates Heredity Nucleic Acids Proteins: Structural support Transport Protection and defense Regulation of metabolic activities Means for movement, growth, development and more 3 9 Amino acids Amino acids have carboxyl and amino groups—they function as both acid and base. a Amine Carboxyl 3 10 Amino acids Amino acids have carboxyl and amino groups—they function as both acid and base. a H3N+ H+ + -COO- + H+ 3 11 Amino Acids Amino acids have carboxyl and amino groups—they function as both acid and base. 3 12 Amino Acids The side chains or R-groups also have functional groups. Amino acids can be grouped based on side chains. 3 13 Classes of Amino Acids • Amino acids can be classified based on the characteristics of their R groups. Five have charged hydrophilic side chains. Five have polar but uncharged side chains. Seven have hydrophobic side chains. Cysteine has a terminal disulfide (—S—S—). Glycine has a single hydrogen atom as the R group. Proline has a modified amino group that forms a covalent bond with the R group, forming a ring. 3 14 Charged Amino Acids Hydrophilic “Water-loving” These hydrophylic amino acids attract ions of opposite charges. 3 15 Polar uncharged Amino Acids Hydrophylic amino acids with polar but uncharged side chains form hydrogen bonds 3 16 Non polar Amino Acids Hydrophobic amino acids Hydrophobic = “Water-hating” 3 17 Special Amino Acids 3 18 Disulfide Bridges 3 19 L- Amino Acids The carbon atom is asymmetrical. Amino acids exist in two isomeric forms: • D-amino acids (dextro, “right”) acids (levo, “left”)—this form is found in organisms • L-amino 3 20 Optical isomers Optical isomers result from asymmetrical carbons. 3 21 Proteins are polymers of Amino Acids • Proteins are synthesized by condensation reactions between the amino group of one amino acid and the carboxyl group of another. This forms a peptide-linkage. • Proteins are also called polypeptides. A dipeptide is two amino acids long; a tripeptide, three. A polypeptide is multiple amino acids long. 3 22 Peptide bond Amino acids bond together covalently by peptide bonds to form the polypeptide chain. Dehydration reaction Dipeptide The peptide bond is inflexible—no rotation is possible. 3 23 Peptide bond • A proteins (polypeptides) has a backbone with side chains extending from it 3 24 Peptide bond • Proteins (polypeptides) are chains with Amino (N) terminus and Carboxyl (C) terminus • A proteins amino-acid sequence is written from N to C. Direction 3 25 Proteins • Proteios (Greek) first place • Proteins are polymers of amino acids. • The building blocks (amino acids) are common to all organisms • Proteins are molecules with diverse structures and functions. • Each different type of protein has a characteristic amino acid composition and order. Amino acids 3 26 Proteins: Polymers of Amino Acids • Proteins are polymers of amino acids. They are molecules with diverse structures and functions. • Each different type of protein has a characteristic amino acid composition and order. • Proteins are also called polypeptides. A dipeptide is two amino acids long; a tripeptide, three. A polypeptide is multiple amino acids long. • <30aa = Peptide; >30aa = Protein • Largest proteins - ~10,000aa • Typical protein - 50-2000aa Amino acids 3 27 Proteins: Polymers of Amino Acids • There are only 20 amino acids but the theoretical number of different proteins is ENORMOUS: 20X20 = 400 distinct di-peptides A protein comprised of 100 amino acid is a small protein. 20100 Different small proteins (more than all the electrons in the entire universe!). Amino acids 3 28 Proteome • Proteome-the entire protein complement of the organism • Yeast = ~6000 different proteins • Human=~30-40,000 different basic proteins with many variations 3 29 A protein’s specific shape determines its function • A protein’s specific shape determines its function • A protein consists of one or more polypeptide chain Folded into a unique shape that determines the protein’s function Folding Nitrogenase, catalyzes biological nitrogen fixation (N2 to NH3) 3 30 Proteins have many possible structures 3 31 Noncovalent Interactions within Proteins Folding of proteins into their final structure is directed by non-covalent interactions More interactions = more stable conformation 3 32 Molten globe 3 33 Hydrogen bonds in proteins 04_06_Hydrogen bonds.jpg Can form in any protein Responsible for secondary structures 3 34 Hydrogen bonds in proteins Between side-chain and backbone Between side-chains Between atoms of backbone 3 35 Protein secondary structures • Hydrogen bonds Between atoms of backbone help proteins fold into characteristic structures 3 36 Beta sheet 3 37 Protein secondary structures • b pleated sheets are peptide regions that lie parallel to each other. • Sometimes the parallel regions are in the same peptide, sometimes the parallel regions are from different peptide strands. • This sheet-like structure is stabilized by hydrogen bonds between N-H groups on one chain with the C=O group on the other. • Spider silk is made of b pleated sheets from separate peptides. 3 38 Alpha Helix 3 39 Alpha Helix • The a helix is a right-handed coil. • The peptide backbone takes on a helical shape due to hydrogen bonds. • The R groups point away from the peptide backbone. • Fibrous structural proteins have a-helical secondary structures, such as the keratins found in hair, feathers, and hooves. 3 40 Four levels of protein structure • There are four levels of protein structure: primary, secondary, tertiary, and quaternary. • The precise sequence of amino acids is called its primary structure. • secondary structures consists of regular, repeated patterns in different regions of the polypeptide chain. • A protein’s tertiary structure is the overall threedimensional shape (conformation) of a polypeptide • When a polypeptide assembles into a complex with additional proteins it acquires a Quaternary Structure. 3 41 Primary structure A protein’s primary structure is the sequence of amino acids forming its polypeptide chains 3 42 Secondary structure • secondary structures consists of regular, repeated patterns in different regions of the polypeptide chain. • This shape is influenced primarily by hydrogen bonds arising between atoms within the polypeptide’s repeating (N-C-C-N-C-C…) backbone • Two common secondary structures are the a helix and the b pleated sheet. 3 43 Tertiary structure • Tertiary structure is the overall three-dimensional shape (conformation) of a polypeptide • The primary determinants of the tertiary structure are the interaction between R groups (side chains). 3 44 Factors determining tertiary structure Factors determining tertiary structure: • The nature and location of secondary structures • Hydrophobic side-chain aggregation and van der Waals forces, which help stabilize them • The ionic interactions between the positive and negative charges deep in the protein, away from water Ionic bonds between charged R groups Hydrophobic interactions Hydrogen Interactions 3 45 Coiled coil motif 3 46 Disulfide bridges Disulfide bridges, which form between cysteine residues can also contribute to stabilization of tertiary structure. 3 47 N.K. 3 48 • Hair styling chemistry Figure 3.6 The Four Levels of Protein Structure (Part 3) 3 50 Quaternary Structure • Quaternary structure results from the ways in which multiple polypeptide subunits bind together and interact. • This level of structure adds to the threedimensional shape of the finished protein. • Hemoglobin is an example of such a protein; it has four subunits. 3 51 Proteins: Polymers of Amino Acids • It is now possible to determine the complete description of a protein’s tertiary structure. • The location of every atom in the molecule is specified in three-dimensional space. Figure 3.7 Three Representations of Lysozyme 3 53 Proteins: Polymers of Amino Acids • Shape is crucial to the functioning of some proteins: Enzymes need certain surface shapes in order to bind substrates correctly. Carrier proteins in the cell surface membrane allow substances to enter the cell. Chemical signals such as hormones bind to proteins on the cell surface membrane. • The combination of attractions, repulsions, and interactions determines the right fit. 3 54 Hemoglobin can bind Oxygen 3 55 Protein structure can change with function Protein structure can change with function • Hemoglobin first binds one O2 molecule • Conformational changes, ionic bonds are broken • Exposure of buried side chains • Enhanced binding of additional O2 • The opposite happens when hemoglobin releases its O2 3 56 Sickle-cell Anemia normal disease 3 57 Sickle cell anemia 3 58 Proteins: Polymers of Amino Acids • Changes in temperature, pH, salt concentrations, and oxidation or reduction conditions can change the shape of proteins. • This loss of a protein’s normal three-dimensional structure is called denaturation. Structural information is in the sequence 3 59 Proteins: Polymers of Amino Acids • Chaperonins are specialized proteins that help keep other proteins from interacting inappropriately with one another. • When a protein fails to fold correctly, serious complications can occur. 3 60 Proteins: Polymers of Amino Acids Some chaperonins help folding; some prevent folding until the appropriate time. 3 61 Aspirin, drug design Hippocrates 5th Century B.C Willow (bark) Arthritis 3 62 Aspirin, drug design Salicin, Converted after digestion into Slicylic acid (1700s) Willow (bark) 3 63 Aspirin, drug design 1897 Felix Hoffmann developed Aspirin (Acetyl salicylic acid) 1971 Mechanism of action discovered by the British pharmacologist, John Robert Vane (awarded both a Nobel Prize in 1982). 3 64 Aspirin, drug design Felix Hoffmann 3 65 Aspirin, drug design Aspirin blocks Cyclooxygenase active site. Cyclooxygenase (Cox) is required for prostaglandin production and inflammation 3 66 Aspirin, drug design Cox 2 is responsible for prostaglandin production in inflammation and pain Aspirin Side effects in stomach are mediated by Cox1 Cox2 Cox1 Cox2 selective inhibitors Celebrex Vioxx (Pfizer) (Merck) Table 3.1 The Building Blocks of Organisms 26% 15% 7% Water 70% 2% 2% 2%