Computer Simulation of Biomolecular Systems of Interest in Bionanotechnology
Date
2019-03-12
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Abstract
Biomolecules, including lipids and enzymes, are of special interest in biotechnology and nano-medicine applications. A knowledge of structure, dynamics, and function of these biomolecular systems is required for development and improvement of drugs and drug delivery systems. Computer simulation, as a complementary technique to experiments, could assist in such an understanding by providing atomistic details on the molecular systems. In this thesis, molecular dynamics (MD) simulation technique was used to study three molecular systems of interest in biotechnological applications: 1) Lamellar phases composed of zwitterionic and ionizable cationic lipids, 2) inverted hexagonal (HII) phases composed of cone-shaped lipids, and 3) a membrane enzyme called CTP:phosphocholine cytidylyltransferase (CCT). First, lipid bilayers composed of POPC and DLin-KC2-DMA (also known as KC2) ionizable cationic lipids were studied as a function of pH, temperature, and mixing ratio. Simulations suggest that neutral KC2 are segregated in the presence of POPC. This segregation was proposed to affect both the internal structure and drug release efficacy of lipid nanoparticles containing KC2. Next, DOPE and POPE HII phases were constructed, simulated, and their structural properties as a function of hydration level and temperature were studied using MD simulations. HII systems are usually challenging to study experimentally, especially at low hydration regimes. Our findings suggest that MD simulation could successfully reproduce structural properties of HII phase in a good agreement with experimental data. Furthermore, a computational protocol for construction of HII molecular systems equivalent to the corresponding HII systems in experiments was proposed. Finally, the auto-inhibition and activation mechanism of CCT enzyme upon attachment or detachment of two autoinhibitory helices was studied. Attachment of autoinhibitory helices were shown to affect the dynamics and consequently the catalytic function of the CCT enzyme. Accordingly, a novel two-part autoinhibition mechanism for CCT enzyme was proposed.
Description
Keywords
Bionanotechnology, Nanomedicine, Drug Delivery, Gene Delivery, Lipid Nano-aggregates, Enzyme, Catalysis, Molecular Dynamics Simulation, Force Field Development, Nanoparticle, Molecular Modeling
Citation
Ramezanpour, M. (2019). Computer simulation of biomolecular systems of interest in bionanotechnology (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.