Smart biomaterials that are self-assembled from peptide amphiphiles (PA) are known to undergo morphological transitions in response to specific physiological stimuli. The design of such customizable hydrogels is of significant interest due to their potential applications in tissue engineering, biomedical imaging, and drug delivery. Using a novel coarse-grained peptide/polymer model, which has been validated by comparison of equilibrium conformations from atomistic simulations, large-scale molecular dynamics simulations are performed to examine the spontaneous self-assembly process. Starting from initial random configurations, these simulations result in the formation of nanostructures of various sizes and shapes as a function of the electrostatics and temperature. At optimal conditions, the self-assembly mechanism for the formation of cylindrical nanofibers is deciphered involving a series of steps: (1) PA molecules quickly undergo micellization whose driving force is the hydrophobic interactions between alkyl tails; (2) neighboring peptide residues within a micelle engage in a slow ordering process that leads to the formation of β-sheets exposing the hydrophobic core; (3) spherical micelles merge together through an end-to-end mechanism to form cylindrical nanofibers that exhibit high structural fidelity to the proposed structure based on experimental data. As the temperature and electrostatics vary, PA molecules undergo alternative kinetic mechanisms, resulting in the formation of a wide spectrum of nanostructures. A phase diagram in the electrostatics-temperature plane is constructed delineating regions of morphological transitions in response to external stimuli.

Peptide amphiphiles are known to form a variety of distinctive self-assembled nanostructures (including cylindrical nanofibers in hydrogels) dependent upon the solvent conditions. Using a novel coarse-grained model, large-scale molecular dynamics simulations are performed on a system of 800 peptide amphiphiles (sequence, palmitoyl-Val3Ala3Glu3) to elucidate kinetic mechanisms of molecular assembly as a function of the solvent conditions. The assembly process is found to occur via a multistep process with transient intermediates that ultimately leads to the stabilized nanostructures including open networks of β-sheets, cylindrical nanofibers, and elongated micelles. Different kinetic mechanisms are compared in terms of peptide secondary structures, solvent-accessible surface area, radius of gyration, relative shape anisotropy, intra/intermolecular interactions, and aggregate size dynamics to provide insightful information for the design of functional biomaterials.

Using a novel coarse-grained model, large-scale molecular dynamics simulations were performed to examine self-assembly of 800 peptide amphiphiles (sequence palmitoyl-V3A3E3). Under suitable physiological conditions, these molecules readily assemble into nanofibers leading to hydrogel construction as observed in experiments. Our simulations capture this spontaneous self-assembly process, including formation of secondary structure, to identify morphological transitions of distinctive nanostructures. As the hydrophobic interaction is increased, progression from open networks of secondary structures toward closed cylindrical nanostructures containing either β-sheets or random coils are observed. Moreover, temperature effects are also determined to play an important role in regulating formation of secondary structures within those nanostructures. These understandings of the molecular interactions involved and the role of environmental factors on hydrogel formation provide useful insight for development of innovative smart biomaterials for biomedical applications.

A novel coarse-grained model is developed to elucidate thermodynamics and kinetic mechanisms of DNA self-assembly. It accounts for sequence and solvent conditions to capture key experimental results such as sequence-dependent thermal property and salt-dependent persistence length of ssDNA and dsDNA. Moreover, constant-temperature simulations on two single strands of a homogeneous sequence show two main mechanisms of hybridization: a slow slithering mechanism and a one-order faster zippering mechanism. Furthermore, large-scale simulations at a high DNA strand concentration demonstrate that DNA self-assembly is a robust and enthalpically driven process in which the formation of double helices is deciphered to occur via multiple self-assembly pathways including the strand displacement mechanism. However, sequence plays an important role in shifting the majority of one pathway over the others and controlling size distribution of self-assembled aggregates. This study yields a complex picture on the role of sequence on programmable self-assembly and demonstrates a promising simulation tool that is suitable for studies in DNA nanotechnology.

A newly developed coarse-grained model called BioModi is utilized to elucidate the effects of temperature and concentration on DNA hybridization in self-assembly. Large-scale simulations demonstrate that complementary strands of either the tetrablock sequence or randomized sequence with equivalent number of cytosine or guanine nucleotides can form completely hybridized double helices. Even though the end states are the same for the two sequences, there exist multiple kinetic pathways that are populated with a wider range of transient aggregates of different sizes in the system of random sequences compared to that of the tetrablock sequence. The ability of these aggregates to undergo the strand displacement mechanism to form only double helices depends upon the temperature and DNA concentration. On one hand, low temperatures and high concentrations drive the formation and enhance stability of large aggregating species. On the other hand, high temperatures destabilize base-pair interactions and large aggregates. There exists an optimal range of moderate temperatures and low concentrations that allow minimization of large aggregate formation and maximization of fully hybridized dimers. Such investigation on structural dynamics of aggregating species by two closely related sequences during the self-assembly process demonstrates the importance of sequence design in avoiding the formation of metastable species. Finally, from kinetic modeling of self-assembly dynamics, the activation energy for the formation of double helices was found to be in agreement with experimental results. The framework developed in this work can be applied to the future design of DNA nanostructures in both fields of structural DNA nanotechnology and dynamic DNA nanotechnology wherein equilibrium end states and nonequilibrium dynamics are equally important requiring investigation in cooperation.