Protein structure

Virtual
modelling
of proteins
Jacek Leluk
Interdyscyplinarne Centrum Modelowania Matematycznego i Komputerowego, Uniwersytet Warszawski
Main functions of proteins (selected):

Enzymes
Immunoglobulins
Transport factors (e.g.hemoglobin)
Hormones, neurotransmitters
Structural and storage proteins
Contractile 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 acids
Amino acid – organic compound that contains amino group
and acidic group (usually it is carboxyl group)
Alanine
General formula
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Amino acid – polypeptide – protein
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Protein chain folding
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Diversity of proteins
Glucagon
ROP protein
Insulin
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Light „harvesting” protein from purple bacteria
Diversity of proteins
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Sequence – structure - function
At 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.
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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 - function
Jacek 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)
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Regular types of structure
(secondary structure)
helix
-helix
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sheet
-chain (-sheet)
Regular types of structure
(secondary structure)
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3D protein structures
Structure-function relationship
Sea anemone - toxin
Snake - toxin
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Bacterial RNase
Mammalian RNase
Rnase inhibitor
(inhibits both RNases)
3D protein structures
Structure-function relationship
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Errors (mutations) and resulting implications
Sickle cell anemia
Sickle 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 –  chain
VHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH

S Hemoglobin –  chain
VHLTPVEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPKVKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFGKEFTPPVQAAYQKVVAGVANALAHKYH
Jacek Leluk
Hemoglobin
Normal
Altered
Mutations and resulting implications
Sickle cell anemia
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Mutations and resulting implications
Sickle cell anemia
Jacek Leluk
Mutations and resulting implications
Sickle cell anemia
Jacek Leluk
Glucagon (pig) – hormone, 29 amino acids
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
Glucagon (synthetic) – hormone, 29 amino acids
HSQGTFTSDYSKYLDSKKAQEFVQWLMNT
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Glucagon (pig) – HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
Glucagon (synth.) – HSQGTFTSDYSKYLDSKKAQEFVQWLMNT
Hydrophobic amino acids:
L, I, V, F, M, Y, (W)
„Gluca con” modelling
Gluca con
LAALIAAVAAAIAAVLRRIAEVLAIVAAL
Jacek Leluk
„Gluca con” design - results
Glucagon (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 work
Jacek Leluk
The value of virtual protein design
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