eprintid: 19060
rev_number: 19
eprint_status: archive
userid: 602
dir: disk0/00/01/90/60
datestamp: 2010-03-30 16:29:10
lastmod: 2015-07-19 03:13:16
status_changed: 2010-03-30 16:29:10
type: thesis
metadata_visibility: show
item_issues_count: 0
creators_name: Watson, S.J.
title: Molecular dynamics simulations of HIV-1 protease
complexed with saquinavir
ispublished: unpub
subjects: 3665
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
therapy for HIV-infected individuals to reduce their viral loads and slow the progression
to Acquired Immune Defi�ciency Syndrome (AIDS). However, mutations readily and rapidly accrue in the protease gene resulting in a reduced sensitivity of the protein
to the inhibitor. In this thesis, molecular dynamics simulations (MDS) were run on
HIV proteases complexed with the protease inhibitor saquinavir, and the strength of
affinity calculated through MMPBSA and normal mode analysis.
We 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
still replicate the change in binding affinity to saquinavir caused by said mutations.
Using 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
the systems resulted in good concurrence for the wild-type (WT) system, but an overall
strong anti-correlation to biochemically derived results. Extension of the WT and
multi-drug resistant (MDR) systems to 50ns yielded no improvement in the correlation
to experimental. However, expansion of these systems to a 10-repetition ensemble MDS
considerably improved the MDR binding affinity compared to the biochemical result.
Principle components analysis on the simulations revealed that a much greater confi�gurational sampling was achieved through ensemble MD than simulation extension.
These data suggest a possible mechanism for saquinavir resistance in the MDR system,
where a transitioning to a lower binding-affinity configuration than WT occurs. Furthermore,
we show that ensembles of 1ns in length sample a significant proportion of
the con�figurations adopted over 10ns, and generate sufficiently similar binding affinities.
date: 2009-12
oa_status: green
thesis_class: doctoral_open
language: eng
thesis_view: UCL_Thesis
dart: DART-Europe
primo: open
primo_central: open_green
full_text_status: public
pages: 223
institution: UCL (University College London)
department: UCL Centre for Virology
thesis_type: Doctoral
citation:        Watson, S.J.;      (2009)    Molecular dynamics simulations of HIV-1 protease complexed with saquinavir.                   Doctoral thesis , UCL (University College London).     Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/19060/1/19060.pdf