CSC 2427 Algorithms for Molecular Biology Spring 2006 Lecture 16 March 10 Lecturer Michael Brudno 16 1 Scribe Jim Huang Overview of proteins Proteins are long chains of amino acids AA which are produced through the operation of translating messenger RNA Proteins play an crucial role in enzymatic activity storage and transport of material signal transduction and many other biological functions There are 20 different AAs that serve as the building blocks for proteins we can therefore think of proteins as sequences of symbols drawn from this alphabet of AAs Each AA is produced from a codon or triplet of nucleotides in the messenger RNA Since the codon AT G is a start codon and AT G also translates to the aminoacid methionine M all proteins begin with a methionine Each AA has a specific chemical structure which contains a carbon backbone and a side chain or R group All 20 different AAs have this same general structure but their side chain groups vary in size shape charge hydrophobicity and reactivity AAs can be classified into a few distinct categories based primarily on their solubility in water AAs with polar side groups are soluble in aqueous solutions and are thus called hydrophilic In contrast AAs with nonpolar side groups avoid water and are said to be hydrophobic These aggregate to form the water insoluble core of proteins The polarity of AA side chains thus is one of the forces responsible for shaping the final three dimensional structure of proteins more on this below AAs in a protein are connected to one another in a linear unbranched chain through peptide bonds A chain of peptide bonds forms the backbone of a protein molecule the various side chain groups for each AA in the protein project outwards from this backbone Fig 16 1 Figure 16 1 An amino acid and a peptide chain figure reproduced from 1 Sidechains R groups hang off the backbone of the peptide chain or polymer Some AAs are more abundant in proteins than other AAs Cysteine tryptophan and methionine are rare AAs together they constitute approximately 5 percent of the AAs in a protein Four AAsleucine serine lysine and glutamic acidare the most abundant AAs totaling 32 percent of all the AA residues in a typical protein However the AA composition of proteins can vary widely from one protein to another Many terms are used to denote the chains formed by polymerization of amino acids A short chain of amino acids linked by peptide bonds and having a defined sequence is a peptide longer peptides are referred to as polypeptides Peptides generally contain fewer than 2030 AAs whereas polypeptides contain as many as 4000 AAs We ll use the term protein for a polypeptide or a complex of polypeptides that has a 3D structure 16 1 CSC 2427 16 2 Lecture 16 March 10 Spring 2006 Protein structure The AA composition of a protein uniquely determines for given environmental conditions the structure of the protein e g two proteins with the same AA sequence will have the same structure for the same conditions There are four hierarchical levels of organization which are used to describe the structure of proteins The primary structure of a protein is simply the linear sequence of AA residues that constitute the polypeptide chain e g M ACILV GT Secondary structure refers to the organization of parts of a polypeptide chain which can assume several different spatial arrangements Without any stabilizing interactions a polypeptide assumes a randomcoil structure However when stabilizing hydrogen bonds form between certain residues the backbone folds periodically into one of two geometric arrangements either an helix which is a spiral rodlike structure see Fig 16 2 or a sheet Fig 16 3 which is a planar structure composed of alignments of two or more short fully extended segments of the backbone Finally U shaped four residue segments stabilized by hydrogen bonds between their arms are called turns They are located at the surfaces of proteins and redirect the polypeptide chain toward the interior Figure 16 2 helix secondary structure of a polypeptide chain the polypeptide backbone is folded into a spiral that is held in place by hydrogen bonds black dots between backbone oxygen atoms and hydrogen atoms Note that all the hydrogen bonds have the same polarity The outer surface of the helix is covered by the side chain R groups figures reproduced from 1 Tertiary structure the next higher level of structure refers to the overall conformation of a polypeptide chain that is the three dimensional arrangement of all the amino acids residues In contrast to secondary structure which is stabilized by hydrogen bonds tertiary structure is stabilized by hydrophobic interactions between the nonpolar side chains and in some proteins by disulfide bonds These stabilizing forces hold the helices strands turns and random coils in a compact internal scaffold Thus a proteins size and shape is dependent not only on its sequence but also on the number 16 2 CSC 2427 Lecture 16 March 10 Spring 2006 Figure 16 3 sheet secondary structure of a polypeptide chain a A simple two stranded sheet with antiparallel strands A sheet is stabilized by hydrogen bonds black dots between the strands The planarity of the peptide bond forces a sheet to be pleated hence this structure is also called a pleated sheet or simply a pleated sheet b Side view of a sheet showing how the R groups protrude above and below the plane of the sheet c Model of binding site in class I MHC major histocompatibility complex molecules which are involved in graft rejection figures reproduced from 1 size and arrangement of its secondary structures For proteins that consist of a single polypeptide chain monomeric proteins tertiary structure is the highest level of organization Quaternary structure describes the number stoichiometry and relative positions of the subunits in a multimeric protein Hemagglutinin is a trimer of three identical subunits other multimeric proteins can be composed of any number of identical or different subunits In a fashion similar to the hierarchy of structures that make up a protein proteins themselves are part of a hierarchy of cellular structures Proteins can associate into larger structures termed macromolecular assemblies Examples of such macromolecular assemblies include the protein coat of a virus a bundle of actin filaments the nuclear pore complex and other large submicroscopic objects Macromolecular assemblies in turn combine with other cell biopolymers like lipids carbohydrates