In Silico Optimisation Of Domain Antibodies Against HSP16.3 From Mycobacterium Tuberculosis

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dc.contributor.authorSoong, Jia Xin
dc.date.accessioned2019-04-17T06:59:15Z
dc.date.available2019-04-17T06:59:15Z
dc.date.issued2018-03
dc.description.abstractHeat shock protein 16.3 (HSP16.3) from Mycobacterium tuberculosis (Mtb) is critical for its survival during latent infection in human, thus making it an attractive target for developing diagnostic and therapeutic strategies. The predicted structure of HSP16.3 was docked against a known HSP hydrophobic probe, namely 4,4′-dianilino-1,1′-binaphthyl-5,5′-disulfonic acid (bisANS) and to the comparative models of HSP16.3 specific single domain antibodies (sdAbs), clone E3 and F1. The binding interactions were further elucidated by free energy calculations. The non-polar interactions were identified as the main force for antigen-antibody association. By using per-residue free energy decomposition and computational alanine scanning, the hot spot residues in E3 (Y391) and F1 (M394, Y396, R397 and M398) had been identified. These residues were subjected to in silico mutagenesis based on suggestions by mCSM-AB webserver. The mutational effects on HSP16.3-dAb complex were analysed using molecular dynamics simulation, free energy calculations and per-residue free energy decomposition. The HSP16.3-E3Y391W complex was predicted to exhibit up to 69% improvement in its binding free energy over the E3 wild type. On the other hand, the highest improvement in F1 wild type was HSP16.3-F1R397N (44%), followed by HSP16.3-F1M398Y (33%), HSP16.3-F1M394E (29%) and lastly HSP16.3-F1M398W (6%). Thus, it can be concluded that the dAbs (E3 and F1) have been successfully optimised against HSP16.3 at in silico level. These findings could serve as guidelines for design of higher affinity dAbs against HSP16.3 at in vitro level in the future.en_US
dc.identifier.urihttp://hdl.handle.net/123456789/8029
dc.language.isoenen_US
dc.publisherUniversiti Sains Malaysiaen_US
dc.subjectHeat shock protein 16.3 (HSP16.3) from Mycobacterium tuberculosisen_US
dc.subjectcritical for its survival during latent infection in humanen_US
dc.titleIn Silico Optimisation Of Domain Antibodies Against HSP16.3 From Mycobacterium Tuberculosisen_US
dc.typeThesisen_US
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