Computational Studies of Molecular Motility, Self-Assembly and Delivery at the Nanoscale

In this thesis, we have studied molecular motility, self-assembly, and delivery at the nanoscale by computational means and in collaboration with several experimental groups. By using quantum chemistry methods and classical molecular dynamics simulations, we have examined: 1) multiple mechanisms by which motion of molecular machines can be controlled at the nanoscale, 2) self-assembly of copolymers into functional nanoconstructs for use in drug delivery, and 3) self-assembly of nanoparticles for separations of liquid mixtures. In 1), we explored the mechanisms to achieve, control, and optimize: rotary and linear motion of synthetic nanoconstructs in different media, intramolecular conformation switching of isolated molecules, pumping of solutions by synthetic molecular “swimmers” and by electroosmosis in nanotubes. We have demonstrated motion in carbon-based molecular structures, ligated nanoparticles, and photoactive isolated molecules and discussed its use in nanoscale devices and machines. In 2), we have modeled the self-assembly of highly PEG-ylated linear and branched (dendron-based) polymers and studied physical properties of the self-assembled micellar aggregates. In collaboration with two experimental groups, we have studied the stabilization of drugs and therapeutic peptides in these micelles. We have identified how different chemical factors contribute to the stabilization of the micelles with solvated therapeutics. In 3), we have studied in collaboration with experimentalists the self-assembly of ligated metallic nanoparticles into planar and bulk superstructures, with the goal to understand the underlying microscopic mechanisms of the superstructure stabilization. We found that the self-assembly (type of packing) of ligated platinum nanocubes is driven by surface charges induced on their surfaces by the ligand-nanoparticle coupling. With the experimentalists we have also examined the use of nanoparticle membranes for separations of liquid mixtures, and found that the passage of molecules through the membranes occurs through nanometer-sized pores with controllable chemistries

Adaptive Evolution of Peptide Inhibitors for Mutating SARS-CoV-2

The SARS-CoV-2 virus is currently causing a worldwide pandemic with dramatic societal consequences for the humankind. In the last decades, disease outbreaks due to such zoonotic pathogens have appeared with an accelerated rate, which calls for an urgent development ofadaptive (smart) therapeutics. Here, we develop a computational strategy to adaptively evolve peptides that could selectively inhibit mutating S protein receptor binding domains (RBDs) of different SARS-CoV-2 viral strains from binding to their human host receptor, angiotensin-converting enzyme 2 (ACE2). Starting from suitable peptide templates, based on selected ACE2 segments (natural RBD binder), we gradually modify the templates by random mutations, while retaining those mutations that maximize their RBD-binding free energies. In this adaptive evolution, atomistic molecular dynamics simulations of the template-RBD complexes are iteratively perturbed by the peptide mutations, which are retained under favorable Monte Carlo decisions. The computational search will provide librariesof optimized therapeutics capable of reducing the SARS-CoV-2 infection on a global scale. <br /

Base Stacking and Sugar Orientations Contribute to Chiral Recognition of Single-Walled Carbon Nanotubes by Short ssDNAs

Single-walled carbon nanotubes (SWNTs) possess exceptional physical and optical properties that make them promising for biomedical and engineering applications. Chirality-pure and enantiopure SWNTs are of particular interest. While single-stranded DNAs were shown to differentially bind and sort SWNTs, the underlying mechanism is not well understood. In this study, we used molecular dynamics simulations to investigate the binding of single and multiple DNA nucleotides to two (7,5) SWNT enantiomers, E1 and E2. Our simulations reveal that nucleotide bases stack closer to the surface of the E2 than the E1 enantiomer. Surprisingly, chiral single and dinucleotides did not exhibit enantiomer-dependent preferences in angular orientations on the SWNT surface. However, ATT trinucleotides exhibited differences in preferred orientations and arrangements of sugar atoms when bound to SWNT enantiomers. Our results suggest that preferred arrangements of DNA sugar moieties may be an important parameter that contributes to the differential binding of DNAs to SWNT enantiomers

Colloidal Nanocube Supercrystals Stabilized by Multipolar Coulombic Coupling

International audienc

Dynamic profiling of double-stranded RNA binding proteins

Double-stranded (ds) RNA is a key player in numer-ous biological activities in cells, including RNA inter-ference, anti-viral immunity and mRNA transport. The class of proteins responsible for recognizing dsRNA is termed double-stranded RNA binding proteins (dsRBP). However, little is known about the molec-ular mechanisms underlying the interaction between dsRBPs and dsRNA. Here we examined four human dsRBPs, ADAD2, TRBP, Staufen 1 and ADAR1 on six dsRNA substrates that vary in length and secondary structure. We combined single molecule pull-down (SiMPull), single molecule protein-induced fluores-cence enhancement (smPIFE) and molecular dynam-ics (MD) simulations to investigate the dsRNA-dsRBP interactions. Our results demonstrate that despite the highly conserved dsRNA binding domains, the dsRBPs exhibit diverse substrate specificities and dynamic properties when in contact with different RNA substrates. While TRBP and ADAR1 have a pref-erence for binding simple duplex RNA, ADAD2 and Staufen1 display higher affinity to highly structured RNA substrates. Upon interaction with RNA sub-strates, TRBP and Staufen1 exhibit dynamic sliding whereas two deaminases ADAR1 and ADAD2 mostly remain immobile when bound. MD simulations pro-vide a detailed atomic interaction map that is largely consistent with the affinity differences observed ex-perimentally. Collectively, our study highlights the diverse nature of substrate specificity and mobility exhibited by dsRBPs that may be critical for their cellular function

Catalytic transport of molecular cargo using diffusive binding along a polymer track

Item does not contain fulltex