Đề tài Protein structure

Virtualmodellingof proteinsJacek Leluk Interdyscyplinarne Centrum Modelowania Matematycznego i Komputerowego, Uniwersytet WarszawskiMain functions of proteins (selected):EnzymesImmunoglobulinsTransport factors (e.g.hemoglobin)Hormones, neurotransmittersStructural and storage proteinsContractile proteins (muscles, flagella)Jacek Leluk Jacek Leluk Protein – a polymer of amino acids. Proteins consists of one or more chains. Some proteins contain other components (sugars, lipids,  nucleotides, metal ions, other compounds...) – proteids. The basic unit of a protein is amino acid. There are 20  biogenic amino acids (genetically encoded).Jacek Leluk Amino acidsAmino acid – organic compound that contains amino group and acidic group (usually it is carboxyl group)AlanineGeneral formulaJacek Leluk Amino acid – polypeptide – proteinJacek Leluk Protein chain foldingJacek Leluk Diversity of proteinsGlucagon ROP proteinInsulin Jacek Leluk Light „harvesting” protein from purple bacteriaDiversity of proteinsJacek Leluk Sequence – structure - functionAt first the central dogma of molecular biology assumed very strict relationship between genetic information, protein structure and function:1 gene 1 sequence 1 structure 1 function At present this dogma is still valid but not in as strict form as before. These relationships are not strictly univocal.e.g. a protein of the same sequence may reveal different secondary and tertiary structures. ???Jacek Leluk All information about protein structure (and function as well) is included in its amino acid sequence, which is unique for each protein. In order to be able to apply these relationships for protein modelling, first we have to learn to read and understand the information „written” in amino acid sequence. The current level of our understanding this „writing” depends on the protein complexity and the prediction accuracy is between 20% and 80%.Sequence – structure - functionJacek Leluk What do we have? Biomolecular databases (genomic, protein and bibliographic) Tools for theoretical analysis of biomolecules Labs for experimental verification of the results Knowledge (theories, hypotheses, theoretical models)Jacek Leluk Regular types of structure(secondary structure)helix-helixJacek Leluk sheet-chain (-sheet)Regular types of structure(secondary structure)Jacek Leluk 3D protein structuresStructure-function relationshipSea anemone - toxinSnake - toxinJacek Leluk Bacterial RNaseMammalian RNaseRnase inhibitor (inhibits both RNases)3D protein structuresStructure-function relationshipJacek Leluk Errors (mutations) and resulting implicationsSickle cell anemiaSickle cell anemia – genetic disease caused by a single amino acid substitution in hemoglobin -chain (one of 146). S hemoglobin has Val instead of Glu in -chain. Homozygotes (HbSS) are lethal, heterozygotes (Hb AS) are anemic, but resistant to malaria. Normal hemoglobin –  chainVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYHS Hemoglobin –  chainVHLTPVEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYHJacek Leluk HemoglobinNormalAlteredMutations and resulting implicationsSickle cell anemiaJacek Leluk Mutations and resulting implicationsSickle cell anemiaJacek Leluk Mutations and resulting implicationsSickle cell anemiaJacek Leluk Glucagon (pig) – hormone, 29 amino acids HSQGTFTSDYSKYLDSRRAQDFVQWLMNT Glucagon (synthetic) – hormone, 29 amino acids HSQGTFTSDYSKYLDSKKAQEFVQWLMNT Jacek Leluk Glucagon (pig) – HSQGTFTSDYSKYLDSRRAQDFVQWLMNT Glucagon (synth.) – HSQGTFTSDYSKYLDSKKAQEFVQWLMNT Hydrophobic amino acids:L, I, V, F, M, Y, (W)„Gluca con” modellingGluca conLAALIAAVAAAIAAVLRRIAEVLAIVAALJacek Leluk „Gluca con” design - resultsGlucagon (pig) – HSQGTFTSDYSKYLDSRRAQDFVQWLMNT Glucagon (synth.) – HSQGTFTSDYSKYLDSKKAQEFVQWLMNT Gluca con – LAALIAAVAAAIAAVLRRIXEVLAIVAAL Jacek Leluk Can we „improve” the Nature at molecular level?What for?Our goal is to get the knowledge about natural mechanisms and then to apply this knowledge for our needs, but not to alter the evolved mechanisms that naturally occur.Jacek Leluk Role and significance of theoretical protein modeling and design Time economy Money economy Work and material economy Increasing our knowledge Supporting the experimental workJacek Leluk The value of virtual protein design=