Biochemistry Notes - Lecture 10, 11
Biochemistry Notes - Lecture 10, 11 Bch4053
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Date Created: 09/26/16
Lecture 10 - Forces in Protein Structures viernes, 23 de septiembre de 2016 11:14 AM Lecture 10, 11, 12 are all the same topcProtein structures Non-bonding forces influencing protein structures • Amino acids of a protein are joined by covalent bondinginteractions. ○ This covalent bond is called a peptide bond • The polypeptide is folded in three dimension bn y n-bondinginteractions.N on- binding forces are those that go "beyond the covalent bond". It goes beyond the molecule itself. T • These interactions can easily be disrupted by extreme pH, temperature, denaturants, reducing reagents. We will discuss the nature of these types of forces: ○ H-bond interactions (12-30 kJ/mol) ○ Hydrophobic Interactions (<40 kJ/mol) § Non-polaramino acids will help dictate the folding of the amino acid and the conjoining of various proteins. ○ Electrostatic Interactions (20 kJ/mol) ○ Van Der Waals Interactions (0.4 -4 kJ/mol) § Every pair of atoms feels these interactions! • The total inter-atomic force acting between two atoms is thes umof all the forces they exert on each other. Hydrogen Bonds: • Hydrogen bonds describe a favorable interaction between a proton bonded to an electronegative atom and an atom carrying lone pairs of electrons: • D-H +A = A-H-A • Acceptors (A): carbonyl (like a peptide bond); hydroxyl groups; amine groups; • Donors (D):a lcohols, any atom with lone pairs of electrons • This interaction is very important for maintaining protein backbone interactions. Hydrophobic interactions: • Hydrophobic interactions minimizes interactions of no-nolar residues with solvent. Thus nonpolar regions of biological macromolcules are often buried in the molecules interior to exclude them from the aqueous milieu. • However non-polar residues can also be found on the surface of a protein. They may participate protein-protein interactions. • This type of interaction is entropy driven. ntropy is favorable - entropy is increasing when the two no-npolar groups are coming together) solvent. Thus nonpolar regions of biological macromolcules are often buried in the molecules interior to exclude them from the aqueous milieu. • However non-polar residues can also be found on the surface of a protein. They may participate protein-protein interactions. • This type of interaction is entropy driven. ntropy is favorable - entropy is increasing when the two no-npolar groups are coming together) ○ There is more entropy due to the interactions with water. The protein residue itself does not become more disordered (in fact it becomes more ordered), it is the release and interactions of water. Electrostatic Interactions: • Charged side chains in protein can interact favorably with an opposing charge of another side chain according to Coulomb’s law: • • F = force, q = charge on the molecule, D = distance between the molecules, r = radius • Examples of favorable electrostatic interaction include that between positively charged lysine and negatively charged glutamic acid. • Salts have the ability to shield electrostatic interactions. ○ The ions will act as a competitor for the interactions • Examples of electrostatic interactions: intramolecular ionic bonds between charged amino acid resides in a proteis uch as glutamic acid/aspartic acid and histidine/arginine/lysine) ; magnesium ATP. ○ Note: DNA charges are always negatively charged - they like to pair with positive ions such as magnesium, potassium, etc. Van der Waals Interactions • van der Waals interaction between two atoms is a result of electron charge distributions of the two atoms. ○ These are "induced-dipole" interactions. ○ Dipoledescribes the asymmetry of charge on an atom. • For atoms that have permanent dipoles: -3 ○ Dipole-dipole interactions (potential energy ~r ) -5 ○ Dipole-induced dipole interactions (potential energy )r • For atoms that have no permanent dipoles: ○ Transient charge distribution inducec omplementary charge distribution (also called dispersion or London dispersion force) (potential energ) ~r ○ Repulsion between two atoms when they approach ea-12other due to overlapping of electron clouds(potential energy ~r ) • In general, the permanent dipole contribution are much less that the dispersion and repulsion forces. Thus the van der Waals potential can be expressed as 1/r -1/r . The characteristics of van der Waals potential is shown below: ○ Repulsion between two atoms when they approach each other due to overlapping of electron clouds(potential energy ~r1) • In general, the permanent dipole contribution are much less that the dispersion and repulsion forces. Thus the van der Waals potential can be expressed as 1/r -1/r . The characteristics of van der Waals potential is shown below: • r i0 the sum ofv an der Waals radiifor the two atoms. Van der Waals forces are attractive forces when r>0r and repulsive when r<0r. The force is the derivative of the yellow curve. The force is blue curve. When they are very far apart, the force is negative. When they just past r0, they begin to repel. The distance between the two atoms is called a "van der Waals radii" • Van der waals radii of common atoms (nm): ○ H 0.1 nm ○ C 0.17 nm ○ N 0.15 nm ○ O 0.14 nm ○ P 0.19 nm ○ S 0.185 nm You don’t have to know these numbers, just recognize the trends. Note ○ how size effects the van der waals radii. ○ The placement of the atoms is not only determined by van der waals reactions. It is the sum of all the interactions! Roles of Amino Acid Sequence in protein structure • Weak forces operate both within the protein structure, between proteins and the water solvent; • All the information necessary for folding the peptide chain into its "native" structure is contained in the amino acid sequence of the peptide; • Certain loci alone the peptide chain act as nuceation points; • Folded proteins avoid local energy minimum • Chaperones in the cells help protein folding. the water solvent; • All the information necessary for folding the peptide chain into its "native" structure is contained in the amino acid sequence of the peptide; • Certain loci alone the peptide chain act as nuceation points; • Folded proteins avoid local energy minimum • Chaperones in the cells help protein folding. Denaturation: • The loss of structure order in biomolecules is called naturation; • The central role of weak forces in biomolecular interactions restricts living systems to a narrow range of physical conditions. • Biomolecules are folded, thus functional, only within a narrow range of environmental conditions such as temperature, ionic strength, and relative acidity; ○ Human proteins are stable generally around 3 -70 degrees, but if you raise the temperature, it will completely lose the structure. The temperature regulates the kinetic energy of the molecules. • Extremes of these conditions disrupt the weak forces essential to maintaining the intricate structure and will lead to loss of their biological functions. ○ You can lose electrostatic interactions, hydrogen bond interactions, etc. Alzheimer Disease: • Alzheimer's disease (AD)is a progressive, neurodegenerative disease characterized by memory loss, language deterioration, impaired visuospatial skills, poor judgment, indifferent attitude, but preserved motor function. • AD usually begins after age 65, however, its onset may occur as early as age 40, appearing first as memory decline and, over several years, destroying cognition, personality, and ability to function. Confusion and restlessness may also occur. ○ The type, severity, sequence, and progression of mental changes vary widely. The early symptoms of AD, which include forgetfulness and loss of concentration, can be missed easily because they resemble natural signs of aging. . • The pathogen responsible for AD is m is-folded proteins, calplaque. The plaque formed in patients brain binds to a receptorin the brain, thus blocking the signals, or currents, that are thought to be involved in learning and memory. ○ The protein is call eta-amyloid peptideand is found in human and animal brain. Plaque is m-folded protein which otherwise have normal function. • MORAL OF THE STORY: Alzheimers comes from misfolded proteins called plaques. AKA, protein folding and interactions are important! Lecture 11: Secondary Structures of Proteins lunes, 26 de septiembre de 2016 11:10 AM The Level of Protein Structure: • Primary Structure (1º)refers to the amino acid sequences of proteins; • Secondary Structure (2º)refers to segments that constitute structural conformities, or regular structures in proteins; • Tertiary Structure (3ºr )efers to the folding of protein chains into a more compact three dimensional shape; • Quaternary Structure (4º) refers to organization of subunits (one subunit is a single polypeptide chain) Restriction by Amide Plane • Atoms in the peptide bond lie in a plane. Resonance stabilization energy of this planar structure is approximately 88 kJ/mol; • Rotation can only occur around the two bonds connected to the Ca atom; • Rotation around the Ca and carbonyl bond is called y ( psi); ○ A psi angle is the rotation between the carbonyl carbon and alpha. ○ Normally phi is first and psi is second. • Rotation around the Ca and nitrogen bond is called f( phi). ○ Phi angle is rotation between C and N Rotation of Amide Planes • If (f,y) are known for all residues, the structure for the entire backbone is known. • Some (f,y) are more likely than others in a folded protein • Positive (f,y) values correspond to clockwise rotation around bonds when viewed from the Ca. Zero is defined when the C=O or N -H bond bisects the-Ca- H angle. ○ (f,y)=(0,180), two carbonyl oxygens are too close; ○ (f,y)=(180,0), two amide groups are overlapping; ○ (f,y)=(0,0), carbonyl oxygen overlaps with amide group Ramachadran Plot: • The plot uses f as horizontal Axis y as vertical axis.(e, y) angle for each residue can be entered on the plot. For folded proteins, thif y) angles cluster in few regions of the plot. The upper left corner beta-sheet values and middle left are a-helices values. Lines signifies the number of amino acids per turn of helix (+ means right-handed, - left-handed) • Normally left handed turns are in an alpha helix. residue can be entered on the plot. For folded proteins, thif y) angles cluster in few regions of the plot. The upper left corner beta-sheet values and middle left are a-helices values. Lines signifies the number of amino acids per turn of helix (+ means right-handed, - left-handed) • Normally left handed turns are in an alpha helix. Cis peptide bonds in proteins -general aspects • If the amino acids are on opposite side they are considered trans. Most amino acids are in a trans configuration. • Occasionally you will see a cis bond. This is if the following residue is a proline residue. ○ Due to its cyclic nature (C alpha attached to the nitrogen), this causes the protein to form a cis structure (an alpha kink) ○ Biologically, this cis and trans has important consequences to the protein structure. In the cell there are cis/trans flipping enzyme s (isomerases) Classes of Secondary Structure: • Terms below define all classes of secondary strctures seen in proteins: ○ Helix § Alpha-helix § 3(10) helix ○ Beta sheet § Parallel § Anti-parallel ○ Beta-bulge ○ Beta turn Alpha helix: • The alpha helix is a helical structure. All alpha helices in proteins arghti- handed; • H-bondpatterns of the alpha helix: ○ Alpha helix: Carbonyl oxygen of the i (I referes to any residue) residue forms H-bond with amide proton of the (i+4) residue (this is 4 amino acids away). So there are n-4H-bonds in a helix of n amino acids; this is independent of side chains. ○ 310 lix: carbonyl oxygen of the i residue forms H-bond with amide proton of the (i+3) residue. 3 residues (or 10 atoms) per turn;- this is very rare. Most proteins in organisms form alpha helices. ○ Prolineis not found in -helix except at the beginning of an a -helix; ○ Helix propensity of an amino acid is a measure of the likelyhood for the amino acid to be in a helix; Glu, Met, Ala, Leu have high propensities; § Its not as much s the nature of the amino acid, but the pattern of the amino acid. ○ Examples of a-helical proteins include a-keratin (structural proteins) and collagen (fibrous protein); ○ Linus Pauling (Nobel Prize in Chemistry, 1954) figured out the structure of keratin helix. § Its not as much s the nature of the amino acid, but the pattern of the amino acid. ○ Examples of a-helical proteins include a-keratin (structural proteins) and collagen (fibrous protein); ○ Linus Pauling (Nobel Prize in Chemistry, 1954) figured out the structure of keratin helix. • Residues per turn: 3.6 • Rise per residue: 1.5 Å; Rise per turn: 5.4 Å; (f,y)=~-(60º,-45º) • The dipole moment of C=O increases, and the dipole moment of -N decreases. The dipole moment of the side chain decreases. We are left with a total dipole moment decrease. Remember dipole measures the asymmetry of the molecule ○ • Helical wheel presentation of a helix can show amino acid distribution along its side. ○ Draw a helical wheel of the sequence “DDRILSWVAELKSE” ○ If you follow the pattern, the yellow position are on one side of the helical wheel and the black are on the other side. Why is this important? ○ IWVL are all non -polar molecules… they form what we call a "hydrophobic strip" that can interact with another alpha helix nearby The Beta Strands: • The beta strands form beta sheets in proteins • H-bond patterns in beta strands: ○ Parallel beta-strands (0.325 nm between two residues) ○ Anti-parallel beta-strands (0.347 nm between two residues) • The carbonyl forms a hydrogen bond with the next strand amide group. ○ If you are parallel, the hydrogen bond is at an angle ○ If you are antiparallel beta strand, the hydrogen bond is colinear. • WHERE ARE THE SIDE CHAINS? The side chains are pointing either up or down (perpendicular) of the sheet) The Beta Sheet: • Formed by beta strands. Note that side chains point away from the sheet while main chains lie on the sheet. Sheets are the most extended form. • Sheets consist of parallel strands are usually larger that those consist of anti - parallel strands. • A sheet consists of parallel strands distribute hydrophobic residues on both sides of the sheet while that consist of antiparallel strands distributes hydrophobic residues on one side • Combinations of interactions will determine the overall structure and function of the protein. It is not just one or two interactions. The Beta Turn (tight turn, or betbend) • Beta turns connect beta strands and reverse the direction of beta strands; • Proline (due to the formation of cis bonds because of cyclic natureand glycine (due to its small side) have high propensity for beta turns; • The carbonyl oxygen of the i residue forms H -bond with the amide proton of of the protein. It is not just one or two interactions. The Beta Turn (tight turn, or betbend) • Beta turns connect beta strands and reverse the direction of beta strands; • Proline (due to the formation of cis bonds because of cyclic natureand glycine (due to its small side) have high propensity for beta turns; • The carbonyl oxygen of the i residue forms H -bond with the amide proton of the (i+3) residue; beta turns are "tight" and only consist of 4 amino acids. • Tight turn promotes formation of antiparallel beta sheets. The Beta Bulge: • Beta bulge occurs between normal b -strands. Comprised of two residues on one strand and one on the other; Here one beta strand is curved a little because it "misses" the hydrogen bond. One amino acid is not bonded to the other strand. • Bulges cause bending of otherwise straight ant -iparallel beta strands; Super secondary Structure: • Hairpinsconnect two antiparallel strands; • Cross-oversconnect two parallel beta strands, most common through an - elix (b-a-b topology). All cross-overs are right-handed. That is, when placing C -side strand closer and pointing right, the connecting a -helix or loop is on the top of the sheet; ○ Place the C strand close to you and the other strand far away fro you, the connection will be going on top of the sheet (not on the back of the sheet) for right handed cross -overs. ○
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