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The 3-Dimensional Structure of Proteins

Objectives. What forces drive the folding of proteins?Describe the levels of protein structure. What are the constraints and determinants of adopting various structures? What are some examples of proteins that display various structural motifs?. Three-dimensional, functional structure is called

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The 3-Dimensional Structure of Proteins

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    1. Chapter 4 The 3-Dimensional Structure of Proteins

    2. Objectives What forces drive the folding of proteins? Describe the levels of protein structure. What are the constraints and determinants of adopting various structures? What are some examples of proteins that display various structural motifs?

    3. Three-dimensional, functional structure is called “native” Folded shape is called “conformation” There are thousands of possible conformations, but not an infinite amount… Conformations are restrained by planarity of peptide bond “allowed” angles

    4. The 4 levels of protein stucture Primary: Linear amino acid sequence Bonds: Covalent Secondary: Local structure; certain “motifs” are common Bonds: Mostly H-bonds Tertiary: Complete 3-D shape Bonds: H-bonds, hydrophobic interactions, ionic bonds, van der Waals interactions, disulfide bonds Quaternary: >1 peptide chains Bonds: Mostly H-bonds

    6. There is no free rotation about the peptide bond due to resonance. This limits the number of possible conformations.

    8. Ramachandran Plot for L-Ala

    9. Secondary Structure The alpha helix Tightly wound, repeating sequence “Right-handed” R-groups are on outside of helix Each twist ? 5.4 Å; 3.6 residues Stabilized by H-bonds between N-H and C=O 3+ residues away a-helices are polar (positive at amino end; negative at carboxyl) Some amino acids are “a-helix breakers” Repeating like-charges Repeating “bulky” groups

    12. Alpha Helix, continued Effects on helical stability: Electrostatic interactions between adjacent residues Steric interference between adjacent residues Interactions between residues 3-4 amino acids away Pro and Gly (helix breakers) Polarity of residues at both ends of helix

    14. Beta Conformation Extended, zigzag conformation Interactions between adjacent amino acids Adjacent strands, H-bonded to one another, lead to beta sheet R-groups protrude opposite of parallel structure

    15. Beta Sheet Parallel ?-sheet Same Amino-carboxyl direction (6.5 Å repeat) Anti-parallel ?-sheet Opposite orientation (7 Å repeat)

    17. ?-turns Interacting strands can be many amino acids apart Turns are 180°; “connect” strands in folded (globular) proteins Interaction is between carbonyl oxygen of aa 1 and amino hydrogen of aa 4 Interior amino acids are not involved; thus, Pro and Gly are often present (Type II turns) Gly: small and flexible Pro: Cis conformation makes inclusion in tight turn favorable…

    19. ?-turns, continued Type I (most common); Type II ALWAYS contain Gly as amino acid #3.

    20. Bond angles (?, ?) describe secondary structure

    22. Tertiary Structure Long range protein structure Interactions between various secondary structural components of protein 2 major classifications: Fibrous (structural proteins) vs. globular

    23. Fibrous Proteins Strong and flexible Hydrophobic Comprise hair, quills, wool, nails, etc. Left-handed helix of intertwined a-helices (of smaller repeat period) confer strength; this forms super-structure called protofilaments, which combine to form fibrils

    24. Alpha-keratin

    25. Collagen Left-handed helix; 3 aa/turn

    26. Collagen Tightly wound left-handed helix Gly-X-Y X = Pro; Y = 4-Hyp*

    27. Globular Proteins Water-soluble Examples: Enzymes (Hexokinase) Transport proteins (Myoglobin) Immune system proteins (Antibodies) More to come on this in subsequent lectures

    29. Protein Domains

    34. Levinthal’s Paradox For random protein folding, make several assumptions: Since there are 2 torsional angles (?, ?), assume 3 stable values for each Assume protein of n amino acids There are then 32n ? 10n possible conformations 1013 conformations can be tested per second (time for single bonds to re-orient) the time for all possible conformations is given by t = 10n/1013 and, for a protein of 100 amino acids, t = 1087 s = 1079 years!!!

    35. Thermodynamics of protein folding

    36. Molten Globule An intermediate state in the folding of protein pathway of a protein that has some secondary and tertiary structure, but lacks the well packed amino acid side chains that characterize the native state of a protein. Observed for many protein under both equilibrium and non-equilibrium conditions. By contrast, for fast folding proteins without intermediates, the search for a core or nucleus is likely to be the rate-determine step; once the core is formed, folding to the native state is fast

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