Berezovsky et al.'s closed loop folding hypothesis suggests that the locks of closed loops (i.e. the ends of the interacting loop) of length ~25-35 residues interact through hydrophobic interactions and that this is a vital event in protein folding. Here we investigate a possible link between the lock residues and drug resistance. The hypothesis is that drug resistance can be limited if the drug binds to the high connectivity regions such as the lock regions. To follow this perspective, the work has moved on to develop an additional method for determining closed loops by using the X-ray crystallographic B-factors as a measure of flexibility. From previous kinetics studies, by using the correlation of folding rate with contact metrics evaluated over the locks of closed loops and their neighbours, we observed that the conservation, particularly maximum proportion is possibly the best method for determining closed loops; we also found that the closed loop hypothesis requires modification to include the neighbours of the lock residues. Berezovsky et al.'s hypothesis has been evaluated using literature results from time-resolved dynamic non-radiative excitation energy transfer measurements for bovine pancreatic ribonuclease A protein (RNase A), as studied by Haas' group. An analysis of the experimental data and molecular dynamics (MD) data in the light of Berezovsky et al.'s hypothesis shows that the MD results are consistent with the experiment results. To investigate the lock residues to look for any additional properties that may help in drug design, we investigated the lock residues of HIV reverse transcriptase and protease by analysing the positions of lock residues vis a vis positions of drug resistant mutations in both enzymes, focussing on the closed loops in accordance to the Berezovsky et al.'s hypothesis. Our results indicate that if these lock residues were to be targeted by drugs, they may be less likely to generate resistance mutations.
Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:654529 |
Date | January 2013 |
Creators | Mohammedali, Hani |
Publisher | University of Essex |
Source Sets | Ethos UK |
Detected Language | English |
Type | Electronic Thesis or Dissertation |
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