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BCH2011: Textbook summary - Lecture 3

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Department
Biology
Course
BCH2011
Professor
Various
Semester
Spring

Description
LECTURE 3 Amino Acids: Proteins are polymers of amino acids, with each amino acid residue joined to its neighbor by a specific type of covalent bond. The term residue reflects the loss of the elements of water when one amino acid is joined to another. Proteins can be broken down (hydrolysed) to their constituent amino acids by a variety of methods. Amino Acids Share Common Features: All 20 of the common amino acids are alpha-amino acids. They have a carboxyl group and an amino group bonded to the same carbon atom (the alpha carbon). They differ from each other in their side chains, or R groups, which vary in structure, size, and electric charge, and which influence the solubility of the amino acids in water. For all the common amino acids except glycine, the alpha-carbon is bonded to four different groups; a carboxyl group, an amino group, an R group, and a hydrogen atom. The alpha-carbon atom is thus a chiral center. Because of the tetrahedral arrangement of the bonding orbitals around the alpha-carbon atom, the four different groups can occupy two unique spatial arrangement, and thus amino acids have two possible stereoisomers. Since they are nonsuperposable mirror images of each other, the two forms represent a class of stereoisomers called enantiomers. All molecules with a chiral center are also optically active-that is, they rotate plane-polarised light. The Amino Acid Residues in Proteins Are L-Stereoisomers: Nearly all biological compounds with a chiral center occur naturally in only one stereoisomer form, either D or L. The amino acid residues in protein molecules are exclusively L stereoisomers. D-amino acids residues have been found in only a few. Virtually all amino acid residues in proteins are L-stereoisomers. Amino Acids Can Be Classified by R Group: The topic can be simplified by grouping the amino acids into five main classes based on the properties of their R groups, particularly their polarity, or tendency to interact with water at biological pH (near pH 7). The polarity of the R groups varies widely, from nonpolar and hydrophobic to highly polar and hydrophilic. Nonpolar, Aliphatic Group: The R groups in this class of amino acids are nonpolar and hydrophobic. The side chains of alanine, valine, leucine, and isoleucine tend to cluster together within proteins, stabilizing protein structure by means of hydrophic interactions. Glycine has the simplest structure. Although it is most easily grouped with the nonpolar amino acids, its very small side chain makes no real contribution to hydrophobic interactions. Methionine, one of the two sulfur containing amino acids, has a slightly nonpolar thioether group in its side chain. Proline has an alipathic side chain with a distinctive cyclic structure. The secondary amino group of proline residues is held in a rigid conformation that reduces the structural flexibility of polypeptide regions containing proline. Aromatic R Groups: Phenylalanine, tyrosine, and tryptophan, with their aromatic side chains, are relatively nonpolar. All can participate in hydrophobic interactions. The hydroxyl group of tyrosine can form hydrogen bonds, and it is an important functional group in some enzymes. Tyrosine and tryptophan are significantly more polar than phenylalanine, because of the tyrosine hydroxyl group and the nitrogen of the tryptophan indole ring. Polar, Uncharged R Groups: The R groups of these amino acids are more soluble in water, or more hydrophilic, than those of the nonpolar amino acids, because they contain functional groups that form hydrogen bonds with water. The polarity of serine and threonine is contributed by their hydroxyl groups, and that of asparagine and glutamine by their amide groups. Cysteine is an outlier here because its polarity, contributed by its sulfhydryl group, is quite modest. It is a weak acid and can make weak hydrogen bonds with oxygen or nitrogen. Cysteine is readily oxidized to form a covalently linked dimeric amino acid called cystine, in which two cysteine molecules or residues are joined by a disulfide bond. The disulfide-linked residues are strongly hydrophobic. Asparagine and glutamine are the amides of two other amino acids also found in proteins – aspartate and glutamate, respectively-to which asparagine and glutamine are easily hydrolysed by acid or base. Disulfide bonds play a special role in the structures of many proteins by forming covalent links between parts of a polypeptide molecule or between two different polypeptide chains. Positively Charged R Groups: The most hydrophilic R groups are those that are either positively or negatively charged. The amino acids in which the R groups have significant positive charge at pH 7.0 are lysine, arginine, and histidine. As the only common amino acid having an ionizable side chain with pKa near neutrality, histidine may be positively charged or uncharged at pH 7.0. His residues facilitate many enzyme-catalysed reactions by serving as proton donors/acceptors. Negatively Charged R Groups: The two amino acids having R groups with a net negative charge at pH 7.0 are aspartate and glutamate, each of which has a second carboxyl group. Amino Acids Can Act as Acids and Bases: The amino and carboxyl groups of amino acids, along with the ionizable R groups of some amino acids, function as weak acids and bases. When an amino acid lacking an ionizable R group is dissolved in water at neutral pH, it exists in solution as the dipolar ion, or zwitterion, which can act as either an acid or a base. Substances having this dual nature are amphoteric (ampholytes). Amino Acids Have Characteristic Titration Curves: Acid-base titration involves the gradual addition or removal of protons. The two ionizable groups of glycine, the carboxyl group and the amino group are titrated with a strong base such as NaOH. The plot has two distinct stages, corresponding to deprotonation of two different groups on glycine. Each of the two stages resembles in shape the titration curve of a monoprotic acid, such as acetic acid, and can be analysed in the same way. At very low pH, the predominant ionic species of glycine is the fully protonated form, +H3N-CH2-COOH. In the first stage of titration, the –COOH group of glycine loses its proton. At the midpoint stage, equimolar concentrations of the proton- donor (_H2N-CH2-COOH) and proton-acceptor (+H3N-CH2-COO-) species are present. For glycine, the pH at the midpoint is 2.34, thus its –COOH group has a pKa of 2.34. As the titration of glycine proceeds, another important point is reached at pH 5.97. Here there is another point of inflection, at which removal of the first proton is essentially complete and removal of the second has just begun. At this pH, glycine is present largely as the dipolar ion (zwitterion) +H3N-CH2-COO-. The second stage of the titration corresponds to the removal of a proton from the –NH3+ group of glycine. The pH at the midpoint of this stage is 9.60, equal to the pKa for the –NH3+ group. The titration is essentially complete at a pH of about 12 at which point the predominant form of glycine is H2N-CH2-COO-. Refer to graph in lecture note 3; Ionisation of amino acid. Titration Curves Predict the Electric Charge of Amino Acids: Another important piece of information derived from the titration curve of an amino acid is the relationship between its net charge and the pH of the solution. At pH 5.97, the point of inflection between two stages in its titration curve, glycine is present predominantly as its dipolar form, fully ionized but with no net electric charge. Refer to graph in lecture note 3; Ionisation of amino acid. The characteristic pH at which the net electric charge is zero is called isoelectric point or isoelectric pH, designated pI. Peptides Are Chains of Amino Acids: Two amino acid molecules can be covalently joined through a substituted amide linkage, termed a peptide bond, to yield a dipeptide. Such a linkage is formed by removal of the elements of water (dehydration) from the alpha-carboxyl group of one amino acid and the alpha-amino group of another. Peptide bond formation is an example of a condensation reaction. To make the reaction thermodynamically more favorable, the carboxyl group must be chemically modified or activated so that the hydroxyl group can be more readily eliminated. An amino acid unit in a peptide if often called a residue (the part left over after losing the elements of water-a hydrogen atom from its amino group and the hydroxyl moiety from its carboxyl group.) In a peptide, the amino acid residue at the end with a free alpha-amino group is the amino terminal (or N-terminal) residue; the residue at the other end, which has a free carboxyl group, is the carboxyl terminal (C-terminal) residue. Although hydrolysis of a peptide bond is an exergonic reaction, it occurs only slowly because it has a high activation energy. As a result, the peptide bonds in proteins are quite stable. Peptides Can Be Distinguished by Their Ionisation Behaviour: Peptides contain only one free alpha-amino group and one free alpha-carboxyl group, at opposite ends of the chain. These groups ionize as they do in free amino acids, although the ionization constants are different because an oppositely charged group is no longer linked to the alpha-carbon. The alpha-amino and alpha-carboxyl groups of all nonterminal amino acids are covalently joined in the peptide bonds, which do not ionize and thus do not contribute to the total acid-base behavior of peptides. However, the R groups of some amino acids can ionize and in a peptide these contribute to the overall acid-base properties of the molecule. Thus the acid-base behavior of a peptide can be predicted from its free alpha-amino and alpha-carboxyl groups combined with the nature and number of its ionizable R groups. LECTURE 4 Overview of Protein Structure: The spatial arrangement of atoms in a protein or any part of a protein is called its configuration. The possible conformations of a protein or protein segment include any structural state it can achieve without breaking covalent bonds. A change in conformation could occur by rotation about single bonds. The need for multiple stable conformations reflects the changes that must take place in most proteins as they bind to other molecules or catalyze reactions. The conformations existing under a given set of conditions are usually the ones that are thermodynamically the most stable – having the lowest Gibbs free energy (G). Proteins in any of their functional, folded conformations are called native proteins. For a vast majority of proteins, a particular structure or small set of structure is critical to function. A protein’s Conformation Is Stabilised Largely by Weak Interactions: In the context of protein structure, the term stability can be defined as the tendency to maintain a native conformation. A given polypeptide chain can theoretically assume countless conformations, and as a result the unfolded state of a protein is characterized by a high degree of conformational entropy. This entropy, and the hydrogen-bonding interactions of many groups in the polypeptide chain with the solvent (water), tend to maintain the unfolded state. The chemical interactions that counteract these effects and stabilize the native conformation include disulfide (covalent) bonds and the weak (non-covalent) interactions. For all proteins of all organisms, weak interactions are especially important in the folding of polypeptide chains into their secondary and tertiary structures. The association of multiple polypeptides to form quaternary structures also relies on these weak interactions. Individual covalent bonds, such as disulfide bonds linking separate parts of a single polypeptide chain, are clearly much stronger than individual weak interactions. Yet, because they are so numerous, it is weak interactions that predominate as a stabilizing force in protein structure. In general, the protein conformation with the lowest free energy (that is, the most stable conformation) is the one with the maximum number of weak interactions. The stability of a protein is not simply the sum of the free energies of formation of the many weak interactions within it. For every hydrogen bond formed in a protein during folding, a hydrogen bond (of similar strength) between the same group and water was broken. Hydrophobic interactions generally predominate. Pure water contains a network of hydrogen bonded H2O molecules. No other molecules has the hydrogen- bonding potential of water, and the presence of other molecules in an aqueous solution disrupts the hydrogen bonding of water. When water surrounds a hydrophobic molecule, the optimal arrangement of hydrogen bonds results in a highly structural shell, or solvation layer, of water around the molecule. The increased order of the water molecules in the solvation layer correlates with an unfavorable decrease in the entropy of the water. However, when nonpolar groups cluster together, the extent of the solvation layer decreases, because each group no longer presents its entire surface to the solution. The result is a favorable increase in entropy. This increase in entropy is the major thermodynamic driving force for the association of hydrophobic groups in aqueous solution. Hydrophobic amino acid side chains therefore tend to cluster in a protein’s interior, away from water. The amino acid sequences of most proteins thus feature a significant content of hydrophobic amino acid side chains. These are positioned so that they are clustered when the protein is folded, forming a hydrophobic protein core. The formation of hydrogen bonds in a protein is driven largely by this same entropic effect. Polar groups can generally form hydrogen bonds with water and hence are soluble in water. Hydrophobic interactions are clearly important in stabilizing conformation; the interior of a structured protein is generally a densely packed core of hydrophobic amino acid side chains. It is also important that any polar or charged groups in the protein interior have suitable partners for hydrogen bonding or ionic interactions. In the tightly packed atomic environment of a protein, one more type of weak interaction can have a significant effect-van der Waals interactions. Van der Waals interactions are dipole-dipole interactions involving the permanent electric dipoles in groups. As atoms approach each other, these dipole-dipole interactions provide an attractive intermolecular force that operates only over a limited intermolecular distance. Van der Waals interactions are weak and individually contribute little to overall protein stability. However, in a well-packed protein, or in an interaction between a protein and another protein or other molecule at a complementary surface, the number of such interactions can be substantial. Hydrophobic residues are largely buried in the protein interior, away from water. The number of hydrogen bonds and ionic interactions within the protein is maximized, thus reducing the number of hydrogen-bonding and ionic groups that are not paired with a suitable partner. The Structure of Proteins – Primary Structure: The structure of large molecules such as proteins can be described at several levels of complexity, arranged in a kind of conceptual hierarchy. Four levels of protein structure are commonly defined. A description of all covalent bonds (mainly peptide bonds and disulfide bonds) linking amino acid residues in a polypeptide chain is its primary structure. The most important element of primary structure is the sequence of amino acid residues. Secondary structure refers to particularly stable arrangements of amino acid residues giving rise to recurring structural patterns. Tertiary structure describes all aspects of the 3D folding of a polypeptide. When a protein has two or more polypeptide subunits, their arrangement in space is referred to as quaternary structure. Each protein has a distinctive number and sequence of amino acid residues. The primary structure of a protein structure of a protein determines how it folds up into its unique 3D structure, and this in turn determines the function of the protein. LECTURE 5: Protein Secondary Structure: The term secondary structure refers to any chosen segment of a polypeptide chain and describes the local spatial arrangement of its main chain atoms, without regard to the position of its side chains or its relationship to other segments. There are a few types of secondary structure that are particularly stable and occur widely in proteins. The most promine
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