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<https://discovery.ucl.ac.uk/id/eprint/19060> <http://purl.org/dc/terms/title> "Molecular dynamics simulations of HIV-1 protease\r\ncomplexed with saquinavir"^^<http://www.w3.org/2001/XMLSchema#string> .
<https://discovery.ucl.ac.uk/id/eprint/19060> <http://purl.org/ontology/bibo/abstract> "Inhibition of the Human Immunode�ficiency virus type-1 (HIV-1) protease enzyme blocks HIV-1 replication. Protease inhibitor drugs have successfully been used as a\r\ntherapy for HIV-infected individuals to reduce their viral loads and slow the progression\r\nto Acquired Immune Defi�ciency Syndrome (AIDS). However, mutations readily and rapidly accrue in the protease gene resulting in a reduced sensitivity of the protein\r\nto the inhibitor. In this thesis, molecular dynamics simulations (MDS) were run on\r\nHIV proteases complexed with the protease inhibitor saquinavir, and the strength of\r\naffinity calculated through MMPBSA and normal mode analysis.\r\nWe show in this thesis that at least 13 residues can be computationally mutated in the proteases sequence without adversely aff�ecting its structure or dynamics, and can\r\nstill replicate the change in binding affinity to saquinavir caused by said mutations.\r\nUsing 6 protease genotypes with an ordered decrease in saquinavir sensitivity we use MDS to calculate drug binding affinity. Our results show that single 10ns simulations of\r\nthe systems resulted in good concurrence for the wild-type (WT) system, but an overall\r\nstrong anti-correlation to biochemically derived results. Extension of the WT and\r\nmulti-drug resistant (MDR) systems to 50ns yielded no improvement in the correlation\r\nto experimental. However, expansion of these systems to a 10-repetition ensemble MDS\r\nconsiderably improved the MDR binding affinity compared to the biochemical result.\r\nPrinciple components analysis on the simulations revealed that a much greater confi�gurational sampling was achieved through ensemble MD than simulation extension.\r\nThese data suggest a possible mechanism for saquinavir resistance in the MDR system,\r\nwhere a transitioning to a lower binding-affinity configuration than WT occurs. Furthermore,\r\nwe show that ensembles of 1ns in length sample a significant proportion of\r\nthe con�figurations adopted over 10ns, and generate sufficiently similar binding affinities."^^<http://www.w3.org/2001/XMLSchema#string> .
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