Molecular dynamics (MD) simulations have made significant contributions to our understanding of biomolecular structures, functions and processes during the last few decades. This proven success is partly due to the level of detail that MD simulations can offer through all-atomistic models with femtosecond level time resolutions. However, their real power in studying increasingly larger systems and biomolecular events with increasingly longer time scales comes from availability of advanced sampling and accelerating techniques. In this study, we utilize some of these advanced techniques to investigate energetics, dynamics and other related properties of diverse biomolecular systems and events as outlined below:

In the first two chapters, we study the interaction of a polyamidoamine (PAMAM) dendrimer, a biocompatible artificial molecule with a highly branched structure, with (i) DNA (Chapter 1) and (ii) α-hemolysin (α-HL), a transmembrane protein nanopore (Chapter 2). Since dendrimers are versatile molecules in their potential uses in various fields of bionanomedicine and bionanotechnology, their interactions with biomolecules are the subject of active research. In Chapter 1, we study the interaction between a third generation (G3) dendrimer and DNA from a biomimetic perspective. To evaluate the possibility of mimicking the protein nonspecific search behavior along DNA, we obtained potential of mean force (PMF) of dendrimer-DNA interaction along a circular reaction coordinate around DNA by using umbrella sampling technique. PMF reveals a free energy minimum when the dendrimer center of mass is on DNA major groove and a free energy energy barrier of 8.5 kcal/mol between dendrimer- DNA minor-groove and dendrimer-DNA major-groove interactions. As such, our result identifies a helical path along DNA major-groove as a possible reaction coordinate for dendrimer sliding along DNA.

Chapter 2 is the result of a collaborative effort with experimentalist Dr. Stephan Howorka from University College London, UK. In this study, we investigate translocation/capture properties of dendrimers of various sizes, G1-G5, through α-hemolysin pore through the use of steered molecular dynamics technique. Computationally, we were able to obtain current blockade values in very close agreement with experimental data.

Finally, in Chapter 3, we find a low energy reaction pathway for the large conformational change of a protein, SecDF, using Targeted Molecular Dynamics method, and obtain potential of mean force for this conformational change. This study helps us relate the SecDF conformational change to its proposed function and explain its mechanism of function.

Studies of translocation of polymers across the pores embedded in membranes draw attention not only to understand such naturally occurring events within the cell, but also to utilize them in various biotechnological applications. In this study, translocation properties of dendrimers of various sizes through alpha-hemolysin, a biological nanopore, are studied through accelerated molecular dynamics simulations. Our results reveal heterogeneity in the dependence of current blockade values on dendrimer size for trans side translocations. We show that not only size but also flexibility of the dendrimers of different generations, as well as their binding site must be collectively taken into account when determining ionic conductance upon translocation.