Date of Degree


Document Type


Degree Name





Sharon M. Loverde

Committee Members

Sebastien Poget

Shaneen M. Singh

Grace Brannigan

Cristiano Dias

Subject Categories

Biochemistry, Biophysics, and Structural Biology


Molecular Dynamics Simulation, Self-Assembly, Microtubule, Peptide Drug Amphiphile


Molecular self-assembly is an energy driven process where randomly organized building blocks interact noncovalently to form highly organized supramolecular nanostructures. In biology, the cytoskeleton is a classic example of a dynamic self-assembly, forming long filamentous structures from monomeric protein subunits. Similarly, the self-assembly process is widely exploited in nanotechnology to build bio-functional nanostructures. In this work, we studied biological (microtubule) and synthetic (peptide drug amphiphile nanotube) self-assembled systems. We utilized long time-scale molecular dynamics simulation to investigate the structural and dynamical properties of these systems.

At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule (MT) is driven by the nucleotide state (GTP vs. GDP) in the β subunit of the tubulin dimers at the MT cap. We used large-scale molecular dynamics (MD) simulations and normal mode analysis (NMA) to characterize the effect of a single GTP cap layer on tubulin octamers composed by two neighboring protofilaments (PFs). We utilized recently reported high-resolution structures of dynamic MTs to simulate a GDP octamer both with and without a single GTP cap layer. We performed multiple replicas of long-time atomistic MD simulations (3 replicas, 0.3μs for each replica, 0.9 μs for each octamer system, and 1.8 μs total) of both octamers. We observed that a single GTP cap layer induces structural differences in neighboring PFs. While one PF possesses a gradual curvature, the second PF possesses a kinked conformation. This conformational difference results in either curling or splaying between these PFs. We suggest these results are caused by the asymmetric strengths of longitudinal contacts between the two PFs. Furthermore, using NMA, we calculated mechanical properties of these octamer systems and found that octamer system with a single GTP cap layer possesses a lower flexural rigidity.

Peptide self-assembly has been used to design an array of nanostructures with functional biomedical applications. Experimental studies have reported nanofilament and nanotube formation from peptide-based drug amphiphiles (DAs). Each DA consists of an anticancer drug camptothecin (CPT) conjugated to a short peptide sequence via a biodegradable disulphide linker. These DAs have been shown to possess an inherently high drug loading with a tunable release mechanism. Recently, long-time atomistic MD simulations of supramolecular nanotubes composed of these DAs have been reported. Based on these all-atomistic simulations we parameterized a coarse grained (CG) model for the DA to study the self-assembly process and the structure and stability of preassembled nanotubes at longer timescales (microseconds). We investigated the self-assembly mechanism using a randomly organized system. We found aggregation between these DAs is an instantaneous process (sub-microsecond) that forms large and ordered assemblies. Additionally, we observed that the radial density distribution of peptides, CPTs, and water molecules and CPT orientation from CG models compared well with results from previously reported atomistic simulations. Furthermore, using all-atomistic MD simulations, we characterized the interaction of the DA nanotube with a model cell membrane. We performed these simulations using advanced sampling method (umbrella sampling). The reaction coordinate used to calculate potential of mean force was the distance between the center of mass of the nanotube and the center of mass of the membrane. Preliminary results indicate that the DA nanotube has a very strong repulsive interaction that can induce a huge bending fluctuation in the membrane. Taken together, these results offer important insights for the rational design of bio-functional supramolecular nanostructures.