(163b) Multi-Scale Molecular Modeling of Fluorescent Organic Nanotubes

Multi-scale Molecular Modeling of Fluorescent Organic
Nanotubes

Arthur Gonzales III¹, Belete Legesse¹, Takeshi Yamazaki²,
Hicham Fenniri^1*

¹Chemical Engineering Department, Northeastern
University, 360 Huntington Avenue, Boston, MA 02115; ²Vancouver Prostate
Centre, 2660 Oak Street, Vancouver, British Columbia, Canada

Rosette
nanotubes (RNTs) are soft organic nanomaterials self-assembled from Watson-Crick
inspired guanine-cytosine (GôC)
hybrid building blocks with complementary hydrogen bonding sites and
stabilizing ¹-¹ interactions and hydrophobic
effects.¹ These materials have substantial design flexibility and a
range of applications, which is partly attributed to their diverse surface
functionalization and a chemically/physically tunable channel for guest
molecule loading. Several studies have established their biocompatibility and
applications in nanomedicine such as in coatings for medical devices and
materials for tissue engineering.² With novel applications in mind
and in an effort to streamline its synthesis, a new tricyclic GôC
motif (Figure 1A) was designed and synthesized to self-assemble into fluorescent
RNT in solution. Verification of the self-assembly to tubular structures and
fluorescence properties are reported elsewhere.³ In this work, classical
molecular modeling techniques were applied to aid in the characterization of
this new RNT, to predict its structure and self-assembly, and to determine its
viability as a drug delivery vehicle.

Molecular dynamics (MD) and the statistical mechanical
theory of solvation, also known as the 3 dimensional reference interaction site
model (3D-RISM) theory were applied to predict the stable conformations of the
motif and RNT. RNT models were built from minimized GôC
motifs and MD simulations were run in different conditions to determine the
stability and probable structure of the nanotubes. 3D-RISM integral equations
were then solved for the system to determine the energetics and to propose a
self-assembly pathway for the RNTs. The self-assembly process was investigated
further by randomly placing GôC motifs on top of a template (a short helical coil RNT),
in a simulation cell and running MD simulations in experimental conditions to
observe the growth of the RNT in silico. In addition, the potential for
drug encapsulation using this novel RNT was tested by loading it with
Gemcitabine, a small molecule drug that is used to treat various carcinomas,
and running MD simulations in physiological conditions to determine the
stability the drug-RNT complex. All simulations were done using the Schršdinger
Materials Science Suite on high performance computers in the Discovery Cluster
of Northeastern University.

The results suggest that this tricyclic GôC
motif can either form helical coils (HC) (Figure 1B) or ring stacks (RS) (Figure
1C) depending on the conditions used in the simulation. Based on molecular
dynamics, the HC configuration of the RNT is more stable than the RS
configuration in all the conditions tested. While the thermodynamics analysis
using 3D-RISM suggests RS is slightly more stable than HC in water. Moreover,
when a RS has stabilized in simulation, the 7-membered rosette conformation
seems more favorable than the 6-membered configuration. The self-assembly
simulations showed that ¹-¹ stacking is the
dominant interaction in the formation of aggregates of the motif at high
temperatures. And for the first time, the
growth of the helical coil RNT from free motifs in the solution was observed in
silico. The stable helical coil seems to drive the alignment of free GôC
motifs to conform to the rest of the RNT. In addition, the switch from HC to RS
was also observed during the self-assembly study when the temperature of the
simulation cell was increased to 70 ¡C. Finally, the MD simulations suggest
that the Gemcitabine-RNT complex (Figure 1D) is stable, making a fluorescent RNT-delivered
Gemcitabine a highly probable solution for drug display and delivery.

Figure: From left to
right: the tricyclic GôC motif; complementary hydrogen bonding sites and ¹-¹ interactions can form
rosette nanotubes as helical coils; or ring stacks with seven motifs per ring;
and the gemcitabine-RNT complex, which was observed to be stable in simulations
at physiological conditions, making this RNT a potential vehicle for drug
display and delivery.

Funding Acknowledgement:

Northeastern University

References:

1.        Fenniri, H. et al.
Helical rosette nanotubes: Design, self-assembly, and characterization. J.
Am. Chem. Soc. 123, 3854Ð3855 (2001).

2.        Chun, A., Moralez, J.,
Webster, T. & Fenniri, H. Helical rosette nanotubes: a biomimetic coating
for orthopedics? Biomaterials (2005).

3.        Legesse,
B., Cho, J., Beingessner, R., Yamazaki, T., Fenniri, H. Fluorescent
Rosette Nanotubes from the C-analogue of the GuanineÐCytosine Motif. MRS
Proceedings. 1796-11 (2015).