Kashif Sadiq
Kashif Sadiq is a Marie Curie post-doctoral research fellow at Universitat Pompeu Fabra. He holds Ba and MSci degrees in Natural Sciences (University of Cambridge, 2001) and a PhD in Theoretical and Computational Biophysics (University College London, 2008). His underpinning research interest lies in the application of computational and theoretical physics in the fundamental understanding of biological processes that span several spatiotemporal scales as well as practical applications towards personalized medicine and clinical decision support. These range from the application of state-of-the-art supercomputing resources to investigate quantum mechanical descriptions of enzyme catalysis, the classical and statistical mechanical investigations of conformational dynamics and folding of proteins to theoretical development of reaction kinetics and non-equilibrium physics of self-organizing processes. He has worked extensively on computational optimization of therapy in drug-resistant HIV, the process of HIV maturation, dynamics of signaling proteins and spontaneous folding processes of intrinsically disordered proteins. He is keen on public scientific dissemination activities from open day outreach programs to short film development. He has served in a voluntary capacity as alternative energy consultant for the IAAAE European Chapter and in various roles for Humanity First. In his spare time he enjoys mountain climbing, traveling and kung fu.
Former Research
- Structural, dynamical and thermodynamical basis of drug resistance in HIV-1 protease using all atom molecular dynamics simulations.
HIV-1 protease is the enzyme responsible for producing mature and infectious particles (virions) of HIV. It works by cleaving newly formed viral precursor poly-proteins leading to viral maturation and infectivity and is therefore one of the main targets for anti-retroviral therapy, with 9 FDA approved drugs currently developed to inhibit it. The problem with applying these drugs as therapies is that because viral replication leads to a large number of mutant viral strains, the strains that are resistant to the inhibitors proliferate, eventually compromising the efficacy of the therapy. Understanding, the molecular basis of how mutant HIV-1 proteases confer resistance helps to design optimized inhibitors that are less prone to resistance. The structure and dynamics of HIV-1 protease wild-type and several mutant strains when bound to a key inhibitor has been investigated in order to show what structural and dynamical components of the interaction between the protease and the inhibitor lead to the mutants binding less well. This has been extended to a thermodynamical investigation to compute absolute and relative binding free energies of different viral strains for a number of inhibitors.
- Development of patient-specific simulation approaches for clinical decision support.
The large number of mutational strains that exist for HIV and the differences in their responses to inhibitor treatment make the problem of deciding optimal treatments complex. Conventionally, the principal mutations of HIV in an infected person can be determined by genotypic assaying and the data fed into clinical decision support systems that use inductive knowledge based methods to proscribe the most effective treatment. This method is limited to accumulated data on existing treatment responses and cannot predict the effect of treatment on novel mutations. An enhanced solution is to complement existing decision support software with predictive models that determine in advance the effect of a given inhibitor treatment for any given mutation. This allows treatment to be tailored to the specific viral-genotypic condition of the patient. Therefore, the computational methodology for determining absolute free energies of binding for a set of inhibitors with any given mutant of HIV-1 protease has been further developed and automated. This in turn has been coupled to existing decision support systems in a new virtual environment under the EU Virolab project.
Current Research
- Energetics and kinetics of conformational changes in HIV-1 protease.
HIV-1 protease is homodimeric C2-symmetric protein with each monomer comprising 99 amino acids. The dimer interface forms the base of the active site containing the catalytic aspartyl dyad and a pair of beta-hairpin chains called the "flaps" close over the active site and mediate access to it. The flaps of the HIV-1 protease need to open in order to accommodate ligands. It is desirable to understand the various modes of flap opening in order to understand better the functionality of the protease as well as to determine alternative classes of inhibitors that may lock the protease in an open conformation. The modes of opening and closing of HIV-1 protease have been investigated using all-atom molecular dynamics simulations in explicit solvent. The use of explicit solvent allows accurate energetics and kinetics to be determined. The results have shown, in agreement with NMR experiment, that two principal modes exist, one of a curled opening of the flaps and one of a wide-opening that could accommodate larger inhibitors. The free energies of flap-opening and closing have been determined as well as the kinetics of the curled-opening mode. The wide-opening event is very rare, occurring only several times in the ensemble of simulations and thus precluding the calculation of energetics or kinetics. However, a movie of the wide-opening dynamics is available here. - Initial auto-binding dynamics of HIV-1 protease.
HIV-1 protease cleaves long poly-protein (Gag-Pol) chains into their individual components proteins. These proteins then form the structural shell of a new virus particle (virion) making it mature and infectious. However, a single monomer of the dimeric protease itself is contained within a Gag-Pol chain. To become fully active, two Gag-Pol chains must dimerize and a pseudo-folded dimeric HIV-1 protease must cleave itself out of this Gag-Pol dimer. The dynamics of how this occurs are being investigated using all-atom ensemble molecular dynamics simulations in explicit solvent. - Non-equilibrium hydrodynamic folding of proteins.
Proteins are the workhorses of all living things. They are involved in virtually all processes within cellular and viral life-form and are subsequently the most diverse form of heteropolymer that exist. To function, most proteins need to fold from a linear unbranched chain of amino acids into a distinct three dimensional shape, specific to their corresponding function. We are investigating the folding of proteins using non-equilibrium molecular dynamics simulations involving hydrodynamic perturbation of resonant vibrational frequencies within proteins. - Intrinsically unstructured proteins.
Whilst most proteins fold into a distinct three dimensional structure in order to function there is now a growing body of evidence showing that some proteins exist in a fundamentally disordered state. Their function is conferred through transient folding and subsequent binding interactions. We are investigating this class of "intrinsically unstructured" proteins using all atom molecular dynamics simulations. - Molecular oligemerization of G-protein coupled receptors (GPCRs).
GPCRs are a large family of transmembrane proteins involved in signal transduction and ultimately cellular response to environmental stimuli. They are involved in a large array of physiological processes such as visual sense, olfactory sense, behaviour regulation through neurotransmitter reception and many others. They are consequently the target for a large percentage of modern medicinal drugs. Recently, GPCRs have been discovered to oligomerize, yet the exact nature of oligomerization and the conditions under which this occurs are unclear. Furthermore, such oligomerization has been implicated in schizophrenia. In collaboration with Jana Selent and using all atom molecular dynamics simulations, we are investigating the oligomerization of GPCRs with an eventual view to determine association differences in a chemotherapeutic environment. - Maturation dynamics of a HIV virion.
Following the maturation of HIV virions is of interest to determine the time taken for a virion to become infectious. The change in this time due to mutation and/or inhibition of the maturation process is of importance to develop therapies that lead to the largest proportion of immature virions after a given time. The modelling of the maturation process requires an understanding of the underlying theoretical reaction kinetics of Gag-Pol polyprotein cleavage by the HIV-1 protease. Such a scheme requires the Michaelis-Menten and specificity rate constants of the full array of Gag-Pol cleavage sites as input and returns the time to maturation of each protein species processed by the protease. In collaboration with Viktor Müller and Peter V. Coveney, we are developing a multiscale systems biology approach to determine the maturation dynamics of virions, where such enzymatic parameters can be determined using all atom molecular dynamics simulations and then fed into a higher level systems biology reaction kinetics scheme to determine the overall maturation of the virion.
General Research Interests
- Equilibrium molecular dynamics modelling of biological systems
- Free energy calculations and entropy determination
- Pathways of molecular association
- Transition state kinetics
- Non-equilibrium methods in complex systems dynamics
- Protein folding using energy flow, dissipative dynamics and fractal percolation
- Entropy in non-equilibrium systems
- Physical origin of self-organizing systems
- Evolutionary systems biology and medicine
- Adaptive fitness landscapes
- Multi-scale integrative modelling of biological systems
- Reaction kinetics models
- Molecular modelling for higher scale parameter refinement
- QM/MM modelling
Publications
- Sadiq, S.K., Konnyu, B., Muller, V. and Coveney, P.V. (2011) Journal of Physical Chemistry B. Reaction Kinetics of Catalyzed Competitive Heteropolymer Cleavage, 115, 11017–11027,
- Buch, I., Sadiq, S. K. and De Fabritiis, G. (2011) Journal of Chemical Theory and Computation. Optimized Potential of Mean Force Calculations for Standard Binding Free Energies, 7, 1765–1772.
- Sadiq, S. K. and De Fabritiis, G. (2010). Proteins: Structure, Function and Bioinformatics. Explicit solvent dynamics and energetics of HIV-1 protease flap-opening and closing, 78:2873–2885.
- Sadiq, S. K., Wright, D. W., Kenway, O. A. and Coveney, P. V. (2010). Journal of Chemical Information and Modeling. Accurate ensemble molecular dynamics binding free energy ranking of multidrug-resistant HIV-1 proteases, 50(5), 890–905.
- R. S. Saksena, B. Boghosian, L. Fazendeiro, O. A. Kenway, S. Manos, M. D. Mazzeo, S. K. Sadiq, J. L. Suter, D. Wright, and P. V. Coveney, (2009). Philosophical Transactions of the Royal Society A. Real science at the petascale, 367, 1897, 2557-2571.
- Sadiq, S. K., Mazzeo, M. D., Zasada, S. J., Manos, S., Stoica, I., Gale, C. V., Watson, S. J., Kellam, P., Brew, S. and Coveney, P. V. (2008). Philosophical Transactions of the Royal Society A. Patient-specific simulation as a basis for clinical decision making. 366, 3199-3299.
- Sadiq, S. K., Zasada, S. J., Wright, D., Stoica, I., and Coveney, P. V. (2008). Journal of Chemical Information and Modelling. Automated molecular simulation based binding affinity calculator for ligand-bound HIV-1 proteases. 48, 1909-1919.
- Stoica, I., Sadiq, S. K. and Coveney, P. V. (2008). Journal of the American Chemical Society. Rapid and accurate prediction of binding free energies for saquinavir-bound HIV-1 proteases. 130, 2639-2648.
- Stoica, I., Sadiq, S. K., Gale, C. V. and Coveney., P. V. (2008). Future HIV Therapy. Virtual physiological human research initiative; the future for rational HIV treatment design? 2(5), 419-425.
- Sadiq, S. K., Wan, S. and Coveney, P. V. (2007). Biochemistry. Insights into a mutation-assisted lateral drug escape mechanism from the HIV-1 protease active site. 46 (51), 14865 -14877.
- Sadiq, S. K., Zasada, S. J. and Coveney, P. V. (2006). Lecture Notes in Computer Science. Grid assisted ensemble molecular dynamics simulations of HIV-1 proteases reveal novel conformations of the inhibitor saquinavir. LNBI 4216, Berthold, M.R., Glen, R. and Fischer I. (eds.) Comp Life 2006, Springer-Verlag, pp.150–161.
- S. K. Sadiq, S. Wan, and P. V. Coveney (2006). Ensemble molecular dynamics of HIV-1 protease with the inhibitor saquinavir: Insights into the molecular basis of drug resistance caused by the G48V and L90M mutations. Antiviral Therapy 11:S151.
- P. V. Coveney, S. K. Sadiq, R. S. Saksena, M. Thyveetil, S. J. Zasada, M. Mc Keown and S. Pickles (2006). A lightweight application hosting environment for grid computing. Proceedings of the UK e-Science All Hands Meeting. pp.217–214.
URL.
- P. V. Coveney, S. K. Sadiq, R. S. Saksena, S. J. Zasada (2006). Constructing chained molecular dynamics simulations of HIV-1 protease using the application hosting environment. Proceedings of the UK e-Science All Hands Meeting. pp.428–431.
URL.
Academic theses
- Molecular dynamics simulation studies of drug resistance in HIV-1 protease. Doctoral thesis (University College London, 2008).
- Effects of plasma ejection from magnetic flares on the X-ray spectra of black hole candidates. Master's thesis (University of Cambridge, 2001).
Conferences and workshops (Oral and Poster)
Wan, S., Wright, D., Sadiq, SK., Zasada, SJ., Coveney, PV. (Oral) Personalized Drug Ranking in Clinical Decision Support. 1st Virtual Physiological Human Conference. Brussels, Belgium. 30/9-1/11/2010
Wright, DW., Sadiq, SK., Kenway, OA., van de Vijver, D., Frentz, D., Coveney, PV., Jha, S. (Oral) Computational Estimation of Binding Affinities for Patient Derived HIV-1 Protease Sequences Bound to Lopinavir. 1st Virtual Physiological Human Conference. Brussels, Belgium. 30/9-1/11/2010
B. Konnyu, T. Turanyi, R. Hirmondo, B. Muller, J. Konvalinka, S. K. Sadiq, P. Coveney, H.-G. Krausslich, V. Muller. (Poster) Reaction kinetics of proteolytic processing during HIV-1 virion maturation. XVIII International AIDS Conference. Vienna, Austria. 18-23/7/2010
I. Buch, T. Giorgino, S.K. Sadiq, G. De Fabritiis. (Oral) Reliable and accurate prediction of ligand binding by high-throughput molecular dynamics simulations. XVIII Jornades de Biologia Molecular, Societat Catalana de Biologia. Barcelona, Spain. 29-30/06/2010
S. Kashif Sadiq, Ileana Stoica, David Wright, Simon J. Watson, Owain Kenway, Paul Kellam and Peter V. Coveney. (Oral) Binding Free Energy Calculations of Ligand-Bound HIV Enzymes for Patient-Specific Decision Support. UK e-Science All Hands Meeting 2008. Edinburgh, UK. 8-11/09/2008.
S. Kashif Sadiq, Ileana Stoica, Simon Watson, David Wright, Owain Kenway, Peter Coveney. (Oral) Patient Specific Clinical Decision Support from Molecular Simulation. EU 6th Framework Virolab Project Meeting. Dagstuhl, Germany. 7/4/2008
S. Kashif Sadiq, Shunzhou Wan, Peter V. Coveney. (Oral) Novel conformations of the inhibitor saquinavir contribute to differential dynamics in characteristic drug resistant mutants of HIV-1 protease over multi-nanosecond timescales. Collaborative Computational Project for Biomolecular Simulation (CCPB) Inaugral Conference. Nottingham, UK. 3-5/1/2007
S. Kashif Sadiq, Ileana Stoica, Peter Coveney. (Oral) On the road towards the Binding Affinity Calculator (BAC). EU 6th Framework Virolab Project Meeting. Amsterdam, Netherlands. 3/12/2006
S. Kashif Sadiq, Shunzhou Wan and Peter V. Coveney. (Oral) Ensemble Molecular Dynamics Simulations of Wildtype and Mutant HIV-1 Proteases Reveal Novel Conformations of the Inhibitor Saquinavir. Molecular Graphics and Modelling Society: Young Modellers' Forum. London, UK. 01/12/2006
S. Kashif Sadiq, S. J. Zasada and P. V. Coveney (Oral) Using the AHE to deploy MD simulations of HIV-1 Protease. Supercomputing 2006. Tampa, Florida, USA. 11-17/11/2006
Sadiq, S. K., Zasada, S. J. and Coveney, P. V. (Oral) Grid assisted ensemble molecular dynamics simulations of HIV-1 proteases reveal novel conformations of the inhibitor saquinavir. Computational Life Sciences II 2006. Cambridge, UK. 27-29/09/2006
- P. V. Coveney, S. K. Sadiq, R. S. Saksena, S. J. Zasada. (Oral) Constructing chained molecular dynamics simulations of HIV-1 protease using the application hosting environment. UK e-Science All Hands Meeting 2006. Nottingham, UK. 18-21/09/2006
S. Kashif Sadiq, Shunzhou Wan and Peter V. Coveney. (Poster) Ensemble molecular dynamics reveals multiple stable conformations of the P2 subsite of saquinavir in the active site of HIV-1 protease. MGMS Meeting Series: Quantum Pharmacology – 30 years on. Oxford, UK. 17-20/09/2006
S. K. Sadiq, S. Wan, and P. V. Coveney. (Poster) Ensemble molecular dynamics of HIV-1 protease with the inhibitor saquinavir: Insights into the molecular basis of drug resistance caused by the G48V and L90M mutations. 15th International HIV Drug Resistance Workshop 2006. Sitges, Spain. 13-17/06/2006
S. Kashif Sadiq, Shunzhou Wan and Peter V. Coveney. (Poster) Ensemble molecular dynamics reveals multiple stable conformations of the P2 subsite of saquinavir in the active site of HIV-1 protease. Molecular Graphics and Modelling Society: Docking and Scoring in Structure Guided Drug Design. Southampton, UK. 5-7/4/2006
Collaborators
Jana Selent at the Research Group on Biomedical Informatics (GRIB) - IMIM, Universitat Pompeu Fabra, Barcelona.
Peter V. Coveney at the Centre for Computational Science, University College London, London.
Viktor Müller at the Department of Plant Taxonomy and Ecology, Eötvös Loránd University, Budapest.