Mechanistic Insights into Dynamics and Thermodynamics of Biomolecular Processes Protein Unfolding and Aggregation DNA Nanomechanics and Drug Delivery

Abstract

Biophysics has seen unprecedented progress, applying concepts from physics to study intriguing biological phenomena. Further advances in this field require fundamental understanding of various processes at the nanoscale and development of appropriate methods and models for different applications. Molecular simulation is playing an ever-increasing role for these purposes. In this thesis, I have examined the structure, dynamics and thermodynamics of various biomolecules of interest using molecular simulation and theoretical modeling. The thesis is organized as follows. In the 1st chapter, I briefly introduce various bioactive molecules and relevant biological phenomena. The 2nd chapter consists of detailed descriptions of simulation methodologies and theoretical frameworks. These include classical molecular dynamics (MD) simulations, advanced sampling techniques for free energy calculations, and various entropy calculation methods. In chapter 3, we propose a carbon nanotube (CNT)-based drug-delivery method. One of the major challenges of nanomedicine and gene therapy is the effective delivery of drugs and genes across cell membranes. Generally, bioactive molecules used as drugs or drug-delivery vehicles cannot passively pass through the cell membrane due to the high penalty associated with membrane rupture. We show via MD simulations that molecules of various shapes, sizes and chemistries can spontaneously enter a membrane-spanning CNT nanopore. We study the thermodynamics of entry of several molecules of interest, such as dendrimers, asiRNA, ssDNA and ubiquitin protein. We show that another free CNT can spontaneously enter the CNT nanopore and eject the encapsulated molecule out of the nanopore. In this way, a macromolecule can be translocated across the cell membrane. We also verify the thermodynamic feasibility of the proposed method. This method should work for other molecules as well, and hence could be potentially useful for drug-delivery applications. The fourth chapter deals with the understanding of...