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Biochemistry Notes Week 5

by: Hannah Hartman

Biochemistry Notes Week 5 Bch4053

Marketplace > Florida State University > Biochemistry > Bch4053 > Biochemistry Notes Week 5
Hannah Hartman
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Notes from biochemistry week 5
General Biochemistry I
Dr. Hong Li
Class Notes
biochemistry, protein, Folding, structure
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This 6 page Class Notes was uploaded by Hannah Hartman on Sunday October 16, 2016. The Class Notes belongs to Bch4053 at Florida State University taught by Dr. Hong Li in Fall 2016. Since its upload, it has received 4 views. For similar materials see General Biochemistry I in Biochemistry at Florida State University.


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Date Created: 10/16/16
Tertiary Structure of Proteins Tertiary folding: The classes of proteins:  Based on structure and solubility, proteins can be grouped into three large classes: o Fibrous proteins - these are only mentioned here; these make up the tissues, skin, bones, etc. These are structural proteins. o Globular proteins - we will be focusing on globular proteins  These catalyze metabolic reactions. o Membrane proteins - these exist on biological membranes. We will not be talking about this now, but in second semester biochemistry we will focus on these. Fibrous Proteins  Fibrous proteins contain polypeptide chains organized parallel along a single axis, producing long fibers or large sheets.  They are mechanically strong, play structural roles in nature  Difficult to dissolve in water o Alpha-keratin and collagen are examples of fibrous proteins o These are extremely long helices that form a helical bundle.  Alpha keratin: o a-keratins are found in hair, fingernails, claws, horns and beaks; o Sequence consists of 311-314 residue alpha helical rod segments capped with non-helical N- and C-termini o Primary structure of helical rods consists of 7-residue repeats, which promotes association of helices o b-keratins are found in silk and consist of gly-ala repeat sequences o Alanine is small and can be packed within the sheets  Collagen: a triple helix o Found in connective tissue in animals including tendons, cartilage, bones, teeth, skin and blood vessels; o 1/3 residues are glycine. Also high in proline and modified amino acids, 4-hydroxy-proline (Hyp), 3-hydroxyproline, and 5-hydroxylysine (Hyl)  Collagen is not just amino acids. It includes variable chemical groups that are modified by other enzymes, such as hydroxyl groups. o These amino acids are unsuited for either alpha helices or beta strands.  Alternatively they form a triple helix, much more extended helix than alpha helix. o Sequence determines structure:  The triple helix is a structure that forms to accommodate the unique composition and sequence of collage. Every third residue faces the crowded center of the helix - only glycine fits here (see next page)  Proline and HyP suit the constraints of phi and psi  Interchain H-bonds involving HyP stabilize helix  Fibrils (formed by types I, II, and III collagen) are further strengthened by intrachain lysine-lysine and interchain hydroxypyridinium crosslinks (see next page) these crosslinks are even stronger than hydrogen bonds!  Collagen fibers are stabilized and strengthened by lys-lys cross-links.  The gap, or hole, region seen in the electron microscope maybe the site of nucleation for the mineralization of bones. Globular Proteins  Globular proteins are more numerous than fibrous proteins in cells. Globular proteins can be classified according to the type and arrangement of secondary structure  Jane Richardson's classification o Antiparallel alpha helix proteins o Parallel or mixed beta sheet proteins o Antiparallel beta sheet proteins o Metal- and disulfide-rich proteins  I will show you three dimensional structures of these types of proteins in class This classification is too simple to reflect the function and evolutionary origins of proteins Structural classification of proteins (SCOP): if you are interested in the folding of these proteins, you can go to the website and check it out! You do not need to know the exact groups or categories though.  SCOP was created to to reflect both structural and evolutionary relatedness of proteins. See: http://scop.mrc-  Family: Clear evolutionarily relationship Proteins clustered together into families are clearly evolutionarily related. Generally, this means that pairwise residue identities between the proteins are 30% and greater.  Superfamily: Probable common evolutionary origin Proteins that have low sequence identities, but whose structural and functional features suggest that a common evolutionary origin is probable are placed together in superfamilies.  Fold: Major structural similarity Proteins are defined as having a common fold if they have the same major secondary structures in the same arrangement and with the same topological connections. Proteins of the same fold, not necessarily of the same primary structure, generally have the same biological function o Example: The currently known all-alpha protein class contain 252 superfamilies, 393 families, and 151 folds. Packing of Globular Proteins:  Secondary structures pack closely to one another and also intercalate with extended polypeptide chains  Most polar residues face the outside of the protein and interact with solvent  Most hydrophobic residues face the interior of the protein and interact with each other  van der Waals’ volume is about 72-77% of the total protein volume; about 25% is not occupied by protein atoms; These cavities provide flexibility in protein conformation and dynamics;  Random coil or loops maybe of importance in protein function (interacting with other molecules, enzyme reactions) Motion in Globular Proteins:  Proteins are not static! Certain movements have consequences in entropy. The greater the movement, the higher the entropy (more energetically favorable).  Protein structures are dynamics; o Atomic motions are random and within short distances (~0.5Å); These motions are arise from kinetic energies and are thus a function of temperature; o Collective motions refer to motions of a group of atoms as a single unit. Usually longer distance and slower; o Conformational changes involve motions of domains or segments in proteins. May occur in response to stimuli. Levinthal's Paradox: This describes how difficult it is for proteins to fold  Consider a protein of 100 amino acids. Assign 2 conformations to each amino acid. The total conformations of the protein is 2 10=1.27x10 . Allow -13 10 sec for the protein to sample through one conformation in search for the overall energy minimum. The time it needs to sample through all conformations is: o (10 )(1.27x10 )=1.27x10 sec = 4x10 years! 9  Levinthal’s paradox illustrates that proteins must only sample through limited conformations, or fold by “specific pathways”. Much research efforts are devoted in searching for the principles of the “specific pathways”. Folding Pathways:  It is hypothesized that protein folding is initiated by reversible and rapid formation of local secondary structures;  Secondary structures then form domains through the cooperative aggregation of folding nuclei;  Domains finally form the final protein through “Molten globule” intermediates. Molecular Chaperones: proteins that hep fold globular proteins:  Molecular Chaperones are a class of proteins that assist protein folding in vivo;  A well characterized chaperonin protein is hsp60 or GroEL; o Humans have many chaperones, where bacteria have few. Chaperones allow the hydrophobic part to be shielded while they are getting folded.  Molecular Chaperones bind effectively to the exposed hydrophobic regions of partially folded structures. An example ofChaperonin:  The bacterial chaperonin, GroEL, is composed of 14 identical subunits arranged in two rings of seven stacked back-to-back with dyad symmetry. Our current understanding on how GroEL assists in protein is that an aggregation-prone polypeptide binds in the open central channel of GroEL together with the co-chaperonin, GroES. o Subsequent ATP hydrolysis triggers the release of both the polypeptide and GroES back into solution, when the polypeptide obtains its native conformation or rebinds to the chaperonin if it is still aggregation-prone.  This is a thermodynamically driven process! The middle parto fthe ring is hydrophobic. The ATP drives the protein folding. Thermodynamics of protein folding:  Folded-unfolded G values will give you the delta G. If a folded protein is negative, the delta G needs to be negative. This is because the energy of the folded protein is lower  DG foldingfoledGunfolded  (H foledunfoldedT(Sfoledunfolded DH foldingDS folding o If we plot this on a diagram, the folded energy is negative and the unfolded energy will be higher. o Delta G is comprised of: enthalpy   from the icontact of the atoms - electrostatic, hydrogen, etc.  favorable interactions have lower delta H values  the internal energy is very low  entropy  These groups have higher entropy when folded  This is unfavorable. A lower delta S in this term becomes a higher -TS.  When a protein is unfolded, it can exist in many states. o The sum of the two is a negative value. This is a battle between enthalpy and entropy. This just considers the chain itself and does not count in the water  In vacuum, polypeptide chains contribute to DH foldingd DS folding  The folded protein is a highly order structure, thus DS folding a negative number and thus –TDS folding a positive quantity in the equation;  In vacuum, protein residues do not interact with solvent water, thus the enthalpy is favored in folded state. DH folding thus a negative quantity.  Overall, the total Gibbs free energy difference is negative, thus favors the folded state. Folding in Water:  Folding nonpolar residues o In aqueous solution, polypeptide chains, as well as solvent, contribute to overall DH foldingd DS foldingo o DG foldingH chain DH chainDS foldingDS folding o The folded protein is a highly order structure, thus DS chains still a negative number and thus –TDS is a positive quantity in the chain equation; Solvent molecules become less organized in folded state, thus DS solvents a large positive number;  The driving force of the folding of the protein is water. o Protein nonpolar residues interact with one another in folded state with weak van der Waals forces, but interact more strongly with solvent through induced dipoles. Thus DH chains positive and favors unfolded state; DH solvent negative however and favors folded state. Folding nonpolar residues is driven by entropy. o In terms of enthalpy, for the chain, unfolded is a more favorable state. In the solvent, folded is the favorable state. o For the chain, it is unfavorable, entropically, to fold the protein. In a water solution, folding is entropically favored.  Folding polar residues o In aqueous solution, polypeptide chains as well as solvent contribute to DH folding DS foldingso  DG foldingH chainDH chainDS foldingDS folding o Folded protein chains are ordered. DS chains still a negative number and thus –TDS chains a positive quantity in the equation; Solvent molecules become less organized in folded state, thus DS solvent a small positive number;  Here the water and the protein are the driving forces. o It is not favored to bury polar residues, but they interact favorably with solvent. Thus DH chains positive and favors unfolded state; DH solvent negative because solvent molecule interact more favorably with themselves. Objectives of Lecture 12: Textbook: Chap. 6  Know the three classes of proteins;  Describe the general features of fibrous proteins and globular proteins;  Describe the structure of collagen. Know the importance of its amino acids in maintaining its triple helix structure;  Identify the class of a globular protein when given its structure in ribbon representation;  Know the kinds and rates of protein motion;  Know the process of protein folding;  Describe the function of molecular chaperones;  Analyze free energies for folding proteins in vacuum and in solvent. Know how enthalpy and entropy contribute to folding different kinds (polar and nonpolar) of residues. Homework: Chap. 6: 3, 4, 5, 6, 7; Questions for Self Study: 3, 5; Additional Problems: 5 Subunit Intreactions and quaternary Structure Forces Driving Quaternary Association: (we skipped over this in class because it was covered in a previous lecture) Advantages of Quaternary Association:  Stability: reduction of surface to volume ratio (surface area is a function 2 3 of r , volume is a function of r );  Genetic economy and efficiency (less DNA is required);  Bringing catalytic sites together;  Cooperativity (required to regulate catalytic activity). (will be described in lecture 26) Insulin: Quaternary Structure Problem  Insulin regulates glucose metabolism. Insufficient insulin lead to diabetes;  Pancreas released (active form) insulin has an quaternary structure of a monomer (two peptide chains covalently linked by disulfide bonds). In vitro produced insulin preferentially form a hexamer which prevents it from binding to insulin receptor;  DNA recombinant techniques were used to convert hexamer form to monomer form that is more clinically efficient. Subunit Interactions:  Many proteins exist in nature as oligomers (noncovalent assemblies of two or more monomer subunits);  Interactions between subunits can be distinguished as either isologous or heterologous;  Isologous interactions use the identical surface of each subunit, which results in a closed homodimer; (head to head – forms a dimer)  Heterologous interactions use nonidentical surface, which results in large polymeric assemblies or cyclic structure. (head to tail – can form a polymer) Symmetry in Subunits:  Cyclic symmetry: single n-fold rotation axis, or Cn  Dihedral symmetry: at least one 2-fold axis perpendicular to an n-fold axis  Cubic symmetry: much less in proteins; seen in virus assembly Hemoglobin:  Hemoglobin transfer oxygen from the lungs through the capillaries to the body.  When hemoglobin binds to oxygen (when oxygen level is high), there is a conformational change.  This motion is due to the binding of oxygen in the middle. This drags 1 particular residue, which changes the entire conformation of the residue. This is the basis for cooperativity.


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