Term
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Definition
Characterized by extensive deposits of misfolded protein (amyloid fibers)
in the brain. These fibers are associated with cell death and loss of brain function. The main component of these deposits is a 42-residue fragment from the Alzheimer’s precursor protein (APP). APP is normally cleaved to produce a 40-residue fragment. In Alzheimer’s disease the peptide is cleaved in the wrong place. The extra two amino acids is enough to convert a normal, soluble peptide
to a toxic, “sticky” peptide that builds up in the brain. Although this may seem like a subtle change,
even more minor changes can lead to equally debilitating diseases. |
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Term
| What percentage of synthesized proteins are unusable due to folding errors? |
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Definition
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Term
| What percentage of monogenic diseases are caused by loss of protein stability? |
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Definition
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Term
| How do protein defects and other mutations cause disease? |
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Definition
- Affect protein structure
- Affect folding mechanism (propensity to misfold) |
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Term
| T or F: Proteins are best thought of as static structures. |
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Definition
| False. Proteins are quite unstable (delta G = 0-10 kcal/mol). They alternate between states of form and unfoldedness (haha). When unfolded though, it can self-assemble into biologically active machines. |
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Term
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Definition
The process by which a protein polymer loops back and forth on itself to form a roughly globular, highly compact structure. Each
polypeptide sequence folds to exactly one structure. Each structure carries out a unique function. |
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Term
| How many amino acids can combine to form proteins? |
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Definition
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Term
| What is bound to the alpha carbon? |
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Definition
| An amino group (NH3+), a carboxyl group (COO-), a hydrogen, and a side chain (R). |
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Term
| What's the pKa of the amino group? |
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Definition
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Term
| What's the pKa of the carboxyl group? |
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Definition
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Term
| What is physiological pH? |
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Definition
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Term
| Which enantiomer is incorporated into proteins by living organisms? |
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Definition
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Term
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Definition
| The start of a protein or polypeptide terminated by an amino acid with a free amine group (-NH2). The convention for writing peptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus. When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus. |
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Term
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Definition
| The end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is translated from messenger RNA, it is created from N-terminus to C-terminus. The convention for writing peptide sequences is to put the C-terminal end on the right and write the sequence from N- to C-terminus. |
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Term
| Conventionally, how are polypeptides written? |
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Definition
| By convention, polypeptides are written left to right from amino to carboxy terminii. |
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Term
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Definition
| A covalent chemical bond formed between two molecules when the carboxyl group of one molecule reacts with the amino group of the other molecule, causing the release of a molecule of water (H2O), hence the process is a dehydration synthesis reaction (also known as a condensation reaction), and usually occurs between amino acids. The resulting C(O)NH bond is called a peptide bond, and the resulting molecule is an amide. |
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Term
| Where is the only place in the polypeptide backbone where rotation is allowed to take place? |
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Definition
| Only about the bonds to and from the central carbon because rotation does not occur about double bonds. |
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Term
| What is required for 3D structure? |
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Definition
1) Diverse side chains
2) Peptide bonds |
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Term
| Why does the peptide bond assume of trans conformation? |
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Definition
| Because of steric clash between alpha carbons. |
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Term
| Why does the peptide bond assume of trans conformation? |
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Definition
| Because of steric clash between alpha carbons. |
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Term
| Why is rotation not allowed about the CO-NH bond? |
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Definition
| Because of the partial double bond character. |
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Term
| T or F: Any combination of phi and psi angles are allowed in nature. |
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Definition
False. Only 10-20 % of possible phi/psi combinations are “allowed”, i.e. found
in nature. This is because at certain phi/psi values, various backbone and side chain atoms approach each
other too closely and begin to repel each other (i.e., occupy the same space). |
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Term
| What does phi and psi values of 180 degrees indicate? |
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Definition
| The polypeptide chain is in a fully extended conformation. |
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Term
| What does phi and psi values of 0 degrees indicate? |
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Definition
| The polypeptide chain is in a fully compacted conformation. |
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Term
| What does a Ramachandran plot indicate? |
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Definition
- Only a small fraction of phi & psi values are allowed (dark grey area in plot). All structures must satisfy this plot, i.e. backbone conformations must lie in the grey regions.
- The limited amount of phi, psi “space” allows only certain structures to form. Alpha helices and beta sheets, the two main secondary structural elements, are found in these grey areas.
- The shapes of these plots arise simply from the way atoms are connected (bond lengths, bond angles, and hard-sphere repulsions).
- Glycine has only a hydrogen for a side chain (very small). Therefore, it experiences fewer repulsions than the other amino acids, as indicated by large grey areas on the right plot. Regions of the polypeptide chain containing Gly will tend to be more flexible. |
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Term
| What is true of regions of a polypeptide containing Gly? |
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Definition
| These regions will be more flexible. |
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Term
| T or F: The presence of peptide bonds in the polymeric backbone is sufficient for globular structure. |
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Definition
False (see nylon-66). The unique structural features of proteins largely arise from the properties of the twenty varieties of side chains extending from the backbone. Since the backbone atoms are identical, any structural differences between polypeptides of similar length are determined by the sequence of R groups. Moreover, in many cases, the function of the protein boils down to the chemistry of one or a few of its amino acids. The rest of the molecule (in these instances) serves as a scaffold to
provide the optimal physical-chemical environment for the reaction to take place. Similarly, the difference between healthy and diseased states is often the replacement of a single amino acid by another in a critical protein. For all of these reasons, it is important to recognize the properties of individual amino acids. |
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Term
| What accounts for the structural differences between polypeptides of different lengths? |
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Definition
| The sequence of R groups. |
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Term
| Which group of amino acids make up the "bricks and mortar" of protein structure? |
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Definition
| The hydrophobic amino acids. |
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Term
| Which amino acids are aliphatic (most hydrophobic)? |
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Definition
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Term
| What are the aromatic, less hydrophobic amino acids? |
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Definition
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Term
| What amino acid is known to pput a "kink" in the polypeptide backbone? |
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Definition
Pro, because X-Pro peptide bonds are frequently found to be cis. Cis peptide bonds can cause the polypeptide chain
to change direction and reverse upon itself. |
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Term
| What effect would Phe, Tyr, and Trp have on a polypeptide chain? |
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Definition
| Probably steric constraints by the large, planar ring systems. |
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Term
| What effect would Val and Ile have on a polypeptide chain? |
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Definition
| Steric constraints resulting from the branching at the beta-carbon. |
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Term
| What is the usefulness of pKa as it applies to protein structure? |
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Definition
pKa is the pH at which one-half of the ionizing groups in question are protonated and the other half are deprotonated. For example, a group with pKa = 4 (such as a carboxylic acid) will be deprotonated at pH 7, and thus
negatively charged at physiological pH. Since the side chains of Glu and Asp give up their protons at pH 7, they are acidic amino acids (recall the Bronsted definition of an acid is a proton donor). A good way to visualize this is that an acidic group likes to give up a proton to the solution, so in order to force it back on, you have to dump extra protons into the solution. To force the protons back onto a
carboxyl group, you need to add enough H+ so that the pH of the solution is 4. |
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Term
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Definition
| One-half of the ionizing groups are charged. |
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Term
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Definition
| The ionizing group is mostly protonated. |
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Term
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Definition
| The ionizing group is mostly deprotonated. |
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Term
| What can be said about the protonation of carboxylic acid (pKa = 4) at physiological pH? |
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Definition
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Term
| What are the acidic amino acids? |
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Definition
Asp and Glu because their carboxylic acid functional groups very much want to
give up a proton at physiological pH. They are therefore usually negatively charged. |
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Term
| What is the only amino acid that can both accept and donate protons readily at physiological pH? |
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Definition
| Histidine, because it is the only molecule that ionizes near pH 7. His is therefore a very important catalytic residue. Its five-membered ring is called an imidazole ring. |
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Term
| What are the basic amino acids? |
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Definition
Lys, Arg, and they have a strong affinity for H+ and become positively charged at physiological pH. Lys
contains a primary amino group and Arg has a bulky guanidino group. |
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Term
| What accounts for the polar side chains of Ser, Thr, Asn, and Gln? |
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Definition
| The presence of electronegative atoms (O, N, S). These atoms have a strong electron withdrawing effect which pulls negative charge from atoms they are bonded to. The resulting partial negative charge on the electronegative atom and partial positive charge on the bonded atom results in a polarized bond. |
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Term
| What are some unique features of cysteine? |
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Definition
Cysteine contains a thiol group (-SH) which can oxidize with another Cys to form a disulfide bridge. In the above reaction, S- is oxidized to S, and H+ is reduced to H. Disulfide formation is the primary way that cross links are introduced into proteins. The thiol group is also the most chemically reactive of all
protein functional groups. It binds to metals and reacts with many organic compounds. The reactive species is usually the thiolate anion (-S-). Cys ionizes to yield the thiolate anion under moderately alkaline conditions (pKa = 8.5). |
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Term
| What are some unique features of glycine? |
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Definition
| Glycine is the only amino acid without a carbon atom side chain. Since the proton side chain is much smaller and less bulky than a carbon side chain, there are many more phi-psi angles available to Gly. The polypeptide backbone has much more flexibility where glycine is present compared to any other amino acid. The proton side chain of Gly is chemically unreactive. |
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Term
| What are some unique features of ? |
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Definition
| Proline can form cis peptide bonds with the amino acid preceding it. Cis peptide bonds tend to introduce a bend or kink in the polypeptide chain. Also, since the side chain bonds directly to the peptide nitrogen, the peptide bond of Pro cannot donate a hydrogen to form a hydrogen bond. |
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Term
| Which amino acid can form a disulfide bridge with itself? |
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Definition
| Cysteine. Disulfide formation is the primary way that cross links are introduced into proteins. |
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Term
| What is the primary way that cross links are introduced into proteins? |
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Definition
| Via disulfide formation between to cysteines. |
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Term
| How can one describe the structural difference between unfolded and native protein molecules? |
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Definition
The structural difference between unfolded and native protein molecules can be described by simple bond rotations. The final 3D shape it adopts is determined by long-range noncovalent interactions between parts of the polypeptide chain distant in primary sequence. Individually, these interactions are weak (<2-3 kcal/mol). Moreover, many of them are present in the unfolded conformation as well. The folded protein is typically only 5-15 kcal/mol more stable than the unfolded molecule; therefore, the forces that act on the two states are nearly balanced. Due to this instability, structure is highly dynamic: proteins
can unfold and refold thousands of times during their lifetimes in the cell. |
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Term
| In what way do proteins fold? |
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Definition
Proteins fold in such a way as to maximize favorable charge-charge and charge-water
interactions. As a result, Asp, Glu, Lys, Arg, and His are often found on the protein surface. This
distribution is responsible for the solubility of globular proteins in water. Charged groups are rarely
found in the interior, and when they are, they are always paired with an opposite charge. Thus, charged
side chains help determine what will be the inside and what will be the outside of the final structure. |
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Term
| What amino acids are generally found on the protein surface? |
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Definition
| Asp, Glu, Lys, Arg, and His. |
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Term
| What is true of charged amino acids? |
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Definition
Charged groups are rarely
found in the interior, and when they are, they are always paired with an opposite charge. Thus, charged
side chains help determine what will be the inside and what will be the outside of the final structure. |
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Term
| What amino acids are generally found in large numbers at the DNA binding site? |
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Definition
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Term
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Definition
| A molecule having partial positive and partial negative charges, without possessing a formal net charge. Molecules with the largest dipoles contain polarizable groups, i.e. electronegative atoms that draw electrons from other atoms. |
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Term
| What's the most common dipole in a protein? |
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Definition
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Term
| What is the most energetically favorable orientation of dipoles? |
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Definition
| When they are aligned in antiparallel fashion, so that the positive end of one dipole forms a favorable electrostatic interaction with the negative end of another (and vice versa). This occurs in beta sheets. |
|
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Term
| What is the dipole orientation of beta sheets? |
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Definition
The dipoles are aligned in antiparallel fashion so that the positive end of one dipole forms a favorable electrostatic interaction with the negative end of
another (and vice versa). This occurs in beta sheets and is the most energetically favorable. |
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Term
| What is the dipole orientation of alpha helices? |
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Definition
Alpha helices align peptide dipoles in
parallel- an unfavorable situation that is often offset by placement of charged side chains at the appropriate termini |
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Term
| Where are most of the H bonds in the folded state? |
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Definition
| Most of the H bonds in the folded state are formed between two groups within the protein (mainly between peptide groups of the backbone). |
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Term
| Where are most of the H bonds in the unfolded state? |
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Definition
| In the unfolded state, they are between protein groups and H2O. |
|
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Term
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Definition
a special case of electrostatic attraction. When hydrogens are bonded to
electronegative atoms (O, N, S), the heavy atom pulls negative electron density from the hydrogen. This results in an excess positive charge on the hydrogen and an excess negative charge on the heavy atom. The H-bond results from the electrostatic attraction between the positively charged hydrogen on
the O-H, N-H, or S-H group and another oxygen, nitrogen, or sulfur atom. The H-bond in this case is uncharged (i.e. there are no formal charges involved), but H-bonds can also be between charged groups. For example, there is considerable H-bonding involved in the Asp-Lys and Glu-Arg ion pairs in the preceding figure. H-bonds have a directional component: they are strongest when the atoms lie in a straight line, as shown above. |
|
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Term
| When are H-bonds the strongest? |
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Definition
| When the atoms lie in a straight line. |
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Term
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Definition
The Van der Waal’s force is present between all atoms, regardless of type. It arises from the electric dipole (dipole = opposite charges separated by a distance, in a molecule with no net charge) that
is induced when two atoms are brought near to each other. The negatively charged electron cloud surrounding the positively charged nucleus is uniform when averaged over time. But at a given instant, the electron density may be temporarily asymmetric, resulting in a transient dipole. This asymmetry can induce a similar dipole in a neighboring atom, if the two atoms are close enough to each other. A net energy bonus is achieved as a result of favorable electrostatic interactions between dipoles. |
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Term
| T or F: Van der Waals energy has little influence on the folding of a protein. |
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Definition
| False. Proteins fold so as to maximize van der Waals energy. This is evident by their tightly packed cores. Almost every atom in the interior is completely surrounded by atoms from neighboring side chains at the optimal van der Waals contact distances. There is very little empty space inside proteins. In fact, proteins contain less empty space than many organic compounds in the crystalline state. Proteins are one of the most tightly packed forms of organic matter. |
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Term
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Definition
| The hydrophobic effect is the major “glue” that holds proteins together. It is also a major driving force for protein interactions with hormones, nucleic acids, and other proteins. The simplest definition of the hydrophobic effect is the tendency of certain molecules to interact with themselves and not with water, when placed in aqueous solutions. These molecules are defined as nonpolar, or hydrophobic. Hydrophobic groups lack charges, charge dipoles, polar groups, and H-bonding groups. Examples of the hydrophobic effect include oil droplets in water, lipid bilayers, and micelles. |
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Term
T or F: Hydrophobic molecules molecules have an unusual attraction for each other?
T or F: Nonpolar molecules and water repel each other? |
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Definition
Both are false! The answer is that H2O has an unusually high attraction for itself, much more so than for hydrophobic compounds. This attraction arises from its polarity and H-bonding properties (it is both an H-bond donor and acceptor). Nonpolar molecules lack the capability of forming H-bonds or other electrostatic interactions. In order to compensate for lost polar and H-bonding interactions, water adopts a different structure in the vicinity of dissolved hydrophobic molecules (ice-like structures called
a ‘clathrates’), compared to the structure of pure water. Formation of clathrates is
energetically unfavorable and is believed to be the origin of the hydrophobic effect. |
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Term
| What accoutns for the tendency of nonpolar molecules to cluster together? |
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Definition
When nonpolar molecules and H2O are allowed to mix in the gas phase, H2O is observed to form highly ordered structures around the nonpolar molecule. A similar ordering is thought to occur around nonpolar solutes dissolved in aqueous solution, although to a lesser degree. Water molecules cannot form H-bonds to nonpolar solutes, so they satisfy their H-bonding potential by forming H-bonded “icebergs” around the nonpolar surface (water molecules are fully H-bonded in clathrates, as they are in ice). Water molecules are more highly ordered in clathrates than in bulk solution, where they can rotate
and move much more freely. The decrease in entropy associated with clathrate formation is largely responsible for the tendency of nonpolar molecules to cluster together, thus reducing nonpolar surface
exposed to H2O. |
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