药物分子设计第八讲

null蛋白质结构（二）蛋白质结构（二）Protein Structure (II)The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitecturePrimary Structure Defined by the amino acid sequence and may include cystines that are formed during cross-linking Tells us the sequence in which the different a-amino acid units are linked. Protein chemists write amino acid sequences with the free -NH2 (or -NH3+) end of the molecule on the left and the free -COOH (or -COO- ) end on the right.The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureSecondary Structure The arrangement of the peptide backbone in space (conformation). The backbone can form regular, repeating structures held together by the attractions between peptide links along it. The secondary structure of a protein includes -helices, -sheets, turns, and random coil, among other less common structure. The two major elements of the secondary structure are the -helix and -sheet, which are stabilized by forming many relatively strong hydrogen bonds .The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureSecondary Structure -helix The -helix is like a narrow-bore tube. The peptide link plates form the wall of the tube with the C atoms projecting a little from the surface. The side chain groups, attached to the C atoms, project outwards from the wall of the tube. The a-helix conformation has a particular stability for two main reasons. Firstly the side chain groups are quite well separated. Secondly, and most importantly, each peptide link is involved in two hydrogen bonds. The C=O is hydrogen bonded to the N_H of the peptide link four units ahead in the primary structure , while it follows that the N_H is hydrogen bonded to the C=O of the peptide link four units behind. The atoms involved are arranged linearly so that the hydrogen bonds are nearly at their maximum strength. Many a-helices are amphipathic.The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureSecondary Structure -helix in order to stabilize the helix dipoleThe Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureSecondary Structure -sheet The polypeptide backbone is nearly fully stretched. It consists of two or more amino acid sequences within the same protein that are arranged adjacently and in parallel, but with alternating orientation such that hydrogen bonds can form between the two strands. Alternate -strands can run in the same direction to give a parallel -sheet or in opposite directions to give an antiparallel -sheet. The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureSecondary Structure Turn A turn is a U-shaped four residue segment of a protein. Turns are stabilized by hydrogen bonds between their arms. Random coil In random coil, the only fixed relationship between amino acids is that between adjacent residues through the peptide bond. The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureSupersecondary structure As the peptide backbone folds back on itself different regions of secondary structure are often brought together. Some of these combinations of -sheets and -helices, and the patterns they make, appear to be common features in many proteins and are called supersecondary structures. The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureTertiary structure The tertiary structure of a protein is the overall 3D architecture of the folded polypeptide chain which also includes the assembly of the various secondary structure elements in 3D. The structure has the best balance of attractive and repulsive forces between different regions of the molecule. The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureTertiary structure Groups of atoms stick together or repel each other in a number of ways.The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureTertiary structureIonic bond Hydrogen bond (3 types shown) Hydrophobic interaction (2 forms shown - lower is cluster type, while upper is Pi-stack type Disulfide bond The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureTertiary structure Globular proteins often have tertiary structures where the molecule appears squashed in the middle, dividing it into two parts held together by a relatively thin stretch of backbone. Protein chemists call the two parts domains and the gap between them a cleft. CleftDomainsactive site of the enzymeThe Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureQuaternary structure Formed between polypeptide chains (called sub-units) and leads to the formation of dimers, trimers, tetramers, etc. The sub-units are stuck to each other by a variety of attractive forces but rarely by covalent bonds The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureQuaternary structure The sub-units may be identical or different; an example is hemoglobin, a globular protein made up of four subunits. The Four Levels of Protein ArchitectureThe Four Levels of Protein ArchitectureSummaryProtein Structure RepresentationsProtein Structure RepresentationsAtoms Color C  white O  red N  blue H  cyan S  yellow P  orange other  gray Protein Structure RepresentationsProtein Structure RepresentationsWireframe Representation Consists of a visualization of the bonding arragement of the atoms of the protein in 3DProtein Structure RepresentationsProtein Structure RepresentationsBall and Stick RepresentationProtein Structure RepresentationsProtein Structure RepresentationsC Trace RepresentationA simpler way to visualize the general fold of a polypeptide chain is to use a C trace. The C trace representation is a line that connects the carbon positions of each amino acid residue. Protein Structure RepresentationsProtein Structure RepresentationsRibbon Representation The ribbon representation provides an overview of the overall folding of the protein. -helices and -sheets are easily recognized.Protein Structure RepresentationsProtein Structure RepresentationsCartoon Representation -helices are represented as cylinders and -sheets as flat arrowsProtein Structure RepresentationsProtein Structure RepresentationsSpace Filling - CPK Representation The atom are shown here as CPK spheres with their volume corresponding to the van der Waals radii of the atom.Protein Structure RepresentationsProtein Structure RepresentationsSurface Representation The surface representation visualizes the molecular envelope of the protein. Protein Structure RepresentationsProtein Structure RepresentationsMolecular SurfaceStructural Classification of ProteinsStructural Classification of ProteinsGlobular proteinMembrane proteinFibrous proteinStructural Classification of ProteinsStructural Classification of ProteinsGlobular Proteins Most proteins which are found in the aqueous, intracellular environment or in the plasma are globular They have a somewhat spherical shape or they are made of several compact domainsStructural Classification of ProteinsStructural Classification of ProteinsHydrophilic Surface and Hydrophobic Core The globular nature of proteins can be explained by their interactions with the surrounding aqueous solvent. Most residues with non-polar side chains are buried in the center, creating the protein's hydrophobic core Most residues with polar side chains remain exposed on the protein surfaceStructural Classification of ProteinsStructural Classification of ProteinsHydrophobic Effect The burial of non-polar residues inside the core of the protein by reducing unfavorable interactions with the surrounding water is known as the "hydrophobic effect" It is considered to be one of the most important forces that contributes to the tertiary and also the quaternary structure of globular proteinsStructural Classification of ProteinsStructural Classification of ProteinsHydration Layer 水化层 Globular proteins in aqueous solutions are surrounded by a hydration layer. Fixed water molecules (red spheres) occur primarily in positions where they can hydrogen bond to polar groups of the proteinStructural Classification of ProteinsStructural Classification of ProteinsMembrane Proteins Proteins that are attached to biological membranes. Adapts its structural features according tot he extent of interaction with the membrane. Structural Classification of ProteinsStructural Classification of ProteinsThe Lipid Bilayer The biological membranes create the cell's physical barriers and compartments, and regulate the molecular traffic across its boundaries. The membrane architecture is the well-known lipid bilayer in which the lipids' hydrophilic polar heads stick out and the hydrophobic tails form the membrane coreStructural Classification of ProteinsStructural Classification of ProteinsMembrane Model A variety of proteins are linked or embedded in the lipid bilayer and play various roles. Altogether, the lipids and the proteins in the membrane are best described by the dynamic system of the "fluid mosaic model" in which the individual lipid and protein molecules are free to diffuse and interact in the plane of the bilayer.Structural Classification of ProteinsStructural Classification of ProteinsMembrane Proteins Types Different proteins associate with membranes to various extents. Peripheral proteins have a fairly shallow penetration of the membrane surface and possess the same structural features as globular proteins. Integral proteins penetrate to deep into the lipid bilayer. These proteins have special structural features.Structural Classification of ProteinsStructural Classification of ProteinsTransmembrane Protein The transmembrane segment of integral membrane proteins must be stable in the hydrophobic hydrocarbon oil-like interior of the lipid bilayer. Most of the amino acid side chains that are on the surface of the transmembrane protein must be non-polar. The polar peptide bond units need to be "covered" by creating hydrogen bonds.Structural Classification of ProteinsStructural Classification of ProteinsTransmembrane Protein -helices and -barrel types are favored.Structural Classification of ProteinsStructural Classification of ProteinsFibrous Proteins Fibrous proteins tend to be long, thin, insoluble in water and arranged to form fibers by associations side by side to construct macroscopic structures - a feature that is important for their structural roles. Most fibrous proteins have regular, extended structures.Structural Classification of ProteinsStructural Classification of ProteinsCollagen Collagen is the most abundant protein of the human body. It is the matrix protein for bones and skin. Collagen exists as a triple helix in which the individual polypeptide chains helices are very extended. Each chain is about 1000 residues long (3000 Å in length).The sequence is characterized by Gly residues in every third position, and is also rich in Pro residues with about half of their side chains being hydroxylated. Covalent linking of Lys residues between the polypeptide chains enhances the strength of this structure.