Structural Bioinformatics: Comparative Modeling. Target T0205 5 th Best in world-wide CASP5 experiment. sb.nrbsc.org. Towards a High-Resolution Understanding of Biology.
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5th Best in world-wide
Structural Biological Analyses can provide the ultimate insight into the mechanism behind a biological function, understand how biological function follows structure.
Aliphatic, Hydrophobic, Important for binding hydrophobic substrates, modulating binding sites
Can lose a proton to act as nucleophiles
Assist in catalyzing reactions
Positively charged amino acids, Can donate a proton as part of enzymatic reactions, general acids, electrophilic
Negatively charged, hydrogen bond acceptors, can abstract a proton as part of enzyme mechanism, general bases, nucleophiles
Can participate in cation-pi interactions, hydrogen bonding, hydrophobic interactions. Tyrosine can donate or accept protons.
Rotation around C-N = phi
Tertiary structure of MsrA
Secondary Structure Elements
Secondary structure refers to the interactions that occur between the C=O and NH groups on amino acids in a polypeptide chain, and form helices, sheets, turns and loops.
sheet: Formed by H-bonds between 5-10 consecutive amino acids in one section of the chain with another 5-10 in another section
Glutathione S-Transferase backbone structures from 100 picosecond MD simulation.
Structure Determination by x-ray crystallography or NMR is still relatively difficult and expensive
Synchrotron in Grenoble, France.
At present there are only 57 synchrotrons in the world
More than 2.5 million proteins have been sequenced (Maroon).
Only 45,000 structures have been experimentally solved (Turquoise).
Structure prediction methods can provide a method to address this disparity
Structural superposition of ALDH Family members
Comparative Protein Models will be increasingly utilized to help solve biological problems
Environmental conditions? pH
Critical Assessment of Structure Prediction (CASP6) Results
Rank and Name: GDT (% correct):
1. Ginalski 70.6
2. Skolnick 70.4
3. Venclovas 68.2
93. Wymore (1PQ3) 57.09
(3 ) Wymore (1GQ6) 70.1
Would have been 3rd best
a) Side chain packing b)Distortions and shifts c) no template
d) Misalignments e) incorrect template
Marti-Renom et al., Ann. Rev. Biophys. Biomol. Struct., 2000, 29:291-325.
Determining the Basis for Stereoselectivity in R- and S-HPCDHs
The enzymatic oxidation of HPC is accomplished through a proton transfer from the substrate to Tyr155 and a hydride transfer from the substrate to NAD.