Synthetic cation-selective nanotube: Permeant cations chaperoned by anions

The ability to design ion-selective, synthetic nanotubes which mimic biological ion channels may have significant implications for the future treatment of bacteria, diseases, and as ultrasensitive biosensors. We present the design of a synthetic nanotube made from carbon atoms that selectively allows monovalent cations to move across and rejects all anions. The cation-selective nanotube mimics some of the salient properties of biological ion channels. Before practical nanodevices are successfully fabricated it is vital that proof-of-concept computational studies are performed. With this in mind we use molecular and stochastic dynamics simulations to characterize the dynamics of ion permeation across a single-walled (10, 10), 36 Å long, carbon nanotube terminated with carboxylic acid with an effective radius of 5.08 Å. Although cations encounter a high energy barrier of 7 kT, its height is drastically reduced by a chloride ion in the nanotube. The presence of a chloride ion near the pore entrance thus enables a cation to enter the pore and, once in the pore, it is chaperoned by the resident counterion across the narrow pore. The moment the chaperoned cation transits the pore, the counterion moves back to the entrance to ferry another ion. The synthetic nanotube has a high sodium conductance of 124 pS and shows linear current-voltage and current-concentration profiles. The cation-anion selectivity ratio ranges from 8 to 25, depending on the ionic concentrations in the reservoirs.We acknowledge the support from the National Health and Medical Research Council and the MAWA Trust

Binding of fullerenes and nanotubes to MscL

Multi-drug resistance is becoming an increasing problem in the treatment of bacterial infections and diseases. The mechanosensitive channel of large conductance (MscL) is highly conserved among prokaryotes. Evidence suggests that a pharmacological agent that can affect the gating of, or block the current through, MscL has significant potential as a new class of antimicrobial compound capable of targeting a range of pathogenic bacteria with minimal side-effects to infected patients. Using molecular dynamics we examine the binding of fullerenes and nanotubes to MscL and demonstrate that both are stable within the MscL pore. We predict that fullerenes will attenuate the flow of ions through MscL by reducing the pore volume available to water and ions, but nanotubes will prevent pore closure resulting in a permanently open pore. Moreover, we confirm experimentally that it is possible to attenuate the flow of ions through MscL using a C60-γ 3 cyclodextrin complex

Continuum modelling of gigahertz nano-oscillators

Fullerenes and carbon nanotubes are of considerable interest throughout many scientific areas due to their unique and exceptional properties, such as low weight, high strength, flexibility, high thermal conductivity and chemical stability. These nanostructures have many potential applications in nano-devices. One concept that has attracted much attention is the creation of nano-oscillators, which can produce frequencies in the gigahertz range, for applications such as ultra-fast optical filters and nano-antennae. In this paper, we provide the underlying mechanisms of the gigahertz nano-oscillators and we review some recent results derived by the authors using the Lennard-Jones potential together with the continuum approach to mathematically model three different types of nano-oscillators including double-walled carbon nanotube, C60-nanotube and C60-nanotorus oscillators

Modelling nanostructures as nano-oscillators and for applications in nanomedicine

The advent of nanotechnology has been the catalyst for considerable advances in industries such as electronics and medicine. The unique physical properties ob- served at the nanoscale has driven numerous investigations into their properties and potential applications. This thesis investigates three aspects of nanotechnology, in particular an alternative formulation for determining the intermolecular force be- tween interacting molecules, nanostructures as nano-oscillators, and nanotubes for applications in nanomedicine. The intermolecular forces between two interacting nanostructures are typically obtained by either summing over all the individual atomic interactions in the dis- crete atom-atom formulation or by using a continuum approach, for which the atoms are assumed to be uniformly distributed over the surface of each molecule. The con- tinuum approach enables highly complicated molecular interactions to be modelled in much less time than the equivalent discrete atom-atom formulation, which can be extremely time consuming. However, a constraint on the continuum approach is that it is mostly applicable to highly symmetrical structures. Motivated by the recent advances in nanotechnology for drug delivery, a hybrid discrete-continuum formu- lation is proposed in this thesis, for which only one of the interacting molecules is discretized and the other is considered to be continuous. The hybrid formulation enables non-regular shaped molecules, such as drugs, to be modelled and this is particularly useful for drug delivery systems which employ carbon nanotubes as car- riers. In a limited comparison the hybrid formulation is shown to compare well to both the discrete atom-atom and continuum formulations. The discovery of carbon nanostructures, such as carbon nanotubes, has gener- ated considerable interest for potential nanomechanical and nanomedical applica- tions. One such device is the high frequency nanoscale oscillator or `gigahertz oscil- lator\u27. Following the concept of these gigahertz oscillators and the recent discovery of toroidal carbon nanotubes or `nanotori\u27, this thesis examines the mechanics of three nano-oscillators constructed from nanotori. In particular, this thesis investi- gates the C60-nanotorus orbiter which comprises a C60 fullerene orbiting around the inside of a nanotorus. Following this, the nanotorus-nanotube oscillator is examined which comprises a carbon nanotorus which is sucked by van der Waals forces onto the carbon nanotube, and subsequently oscillates along the nanotube axis. Finally, the carbon nanotorus-nanosector orbiter is investigated, in which a small sector of nanotorus orbits around the inside of a second seamless nanotorus of larger radius. These nanotori-based oscillators or orbiters are yet to be constructed and the pur- pose is to assess their feasibility by examining the dominant mechanics. One of the most exciting applications of nanotechnology is the proposed use in drug delivery, and in particular the targeted delivery of drugs using nanotubes. This means of targeted delivery would have significant implications for the future treatment of patients, particularly those suffering from cancer. Understanding the encapsulation and expulsion of drug molecules from nanocarriers is vital for the de- velopment of nanoscale drug delivery. This thesis examines theoretically the loading of molecular cargo into single-walled nanotubes, and the mechanics of a proposed nanosyringe which could be used to directly deliver drugs to cells. In particular, this thesis investigates the suction and acceptance of the anticancer drug molecules cisplatin, paclitaxel and doxorubicin into a carbon nanotube, and the effect on the encapsulation behaviour of alternative nanotube materials, which may be more bio- compatible. In particular, the materials boron nitride, silicon and boron carbide are investigated and compared to the corresponding analysis for the carbon nanotube. Finally, an alternative drug delivery mechanism is investigated, namely a proposed nanosyringe constructed from a double-walled carbon nanotube. For each of these nanomedical applications specific nanotube radii are determined for acceptance and maximum drug uptake, and some overall design guidelines are provided. In summary, the original contributions contained in this thesis are: the develop- ment of the hybrid discrete-continuous method; the concepts of the C60-nanotorus, nanotorus-nanotube and nanotorus-nanosector oscillators; the first mathematical examination for the encapsulation of drug molecules into nanotubes; and the con- cept of a double-walled carbon nanosyringe. These nanomechanical and nanomed- ical applications of nanostructures present exciting possibilities, but there are many practical challenges that need to be overcome before these nanodevices can be real- ized. However, this thesis presents a theoretical study which might facilitate their future development

The Bound Structures of 17β-Estradiol-Binding Aptamers

DNA aptamers can exhibit high affinity and selectivity towards their targets, but the aptamer–target complex structures are rarely available from crystallography and often difficult to elucidate. This is particularly true of small molecule targets, including 17β-estradiol (E2), which is becoming one of the most widely encountered endocrine-disrupting chemicals in the environment. Using molecular dynamics simulations, we demonstrate that E2 binds to a thymine loop region common to all E2-specific aptamers in the literature. Analyzing these structures allows us to design new E2 binding sequences. As well as illuminating the essential sequence and structural factors for generating specificity for E2, we demonstrate the effectiveness of molecular dynamics simulations for aptamer science

Conductance properties of the inwardly rectifying channel, Kir3.2: Molecular and 2 Brownian dynamics study

Using the recently unveiled crystal structure, and molecular and Brownian dynamics simulations, we elucidate several conductance properties of the inwardly rectifying potassium channel, Kir3.2, which is implicated in cardiac and neurological disorders. We show that the pore is closed by a hydrophobic gating mechanism similar to that observed in Kv1.2. Once open, potassium ions move into, but not out of, the cell. The asymmetrical current-voltage relationship arises from the lack of negatively charged residues at the narrow intracellular mouth of the channel. When four phenylalanine residues guarding the intracellular gate are mutated to glutamate residues, the channel no longer shows inward rectification. Inward rectification is restored in the mutant Kir3.2 when it becomes blocked by intracellular Mg2 +. Tertiapin, a polypeptide toxin isolated from the honey bee, is known to block several subtypes of the inwardly rectifying channels with differing affinities. We identify critical residues in the toxin and Kir3.2 for the formation of the stable complex. A lysine residue of tertiapin protrudes into the selectivity filter of Kir3.2, while two other basic residues of the toxin form hydrogen bonds with acidic residues located just outside the channel entrance. The depth of the potential of mean force encountered by tertiapin is - 16.1 kT, thus indicating that the channel will be half-blocked by 0.4 μM of the toxin

Carbon nanotube as a gramicidin analogue

We have designed a carbon nanotube that is selectively permeable to monovalent cations, binds divalent cations and rejects anions. The nanotubes, with an effective radius of 4.53 and length of 36 , are terminated with hydrogen atoms and are exohydrogenated in two regions near the entrance and exit. Using molecular and stochastic dynamics simulations we examine the free energy, current-voltage-concentration profiles and ion binding sites. The characteristics of this channel are comparable to the antibiotic gramicidin-A, but the potassium current is six times larger. At 40 mM calcium concentration the current is reduced from 26 pA to 4 pA due to a calcium ion binding at the channel entrance

Orbiting nanosectors inside carbon nanotori

The notion of nanotransport or nanomotion is presently a theoretical concept only, in that no one has actually observed the phenomena in an experimental context. For example, the oscillatory motion of one carbon nanotube sliding inside another is predicted on the basis of molecular dynamics studies, and the authors have provided some elementary modelling of the phenonmena. More recently, the authors have modelled a C60 fullerene orbiting inside a nanotori. The related problem of a carbon nanotorus–nanosector oscillator or orbiter is examined, in which a small sector of a nanotorus orbits inside a second seamless nanotorus of larger radius. Using elementary mechanical principles and applied mathematical modelling techniques, we determine the equilibrium configuration for a number of carbon nanotorus–nanosector oscillators and subsequently investigate their operating frequencies. In line with carbon nanotube oscillators, the proposed analysis predicts orbiting frequencies in the gigahertz range.T. A. Hilder and J. M. Hil

Conduction and block of inward rectifier K+ channels: Predicted structure of a potent blocker of kir2.1

Dysfunction of Kir2.1, thought to be the major component of inward currents, IK1, in the heart, has been linked to various channelopathies, such as short Q-T syndrome. Unfortunately, currently no known blockers of Kir2.x channels exist. In contrast, Kir1.1b, predominantly expressed in the kidney, is potently blocked by an oxidation-resistant mutant of the honey bee toxin tertiapin (tertiapin-Q). Using various computational tools, we show that both channels are closed by a hydrophobic gating mechanism and inward rectification occurs in the absence of divalent cations and polyamines. We then demonstrate that tertiapin-Q binds to the external vestibule of Kir1.1b and Kir2.1 with Kd values of 11.6 nM and 131 μM, respectively. We find that a single mutation of tertiapin-Q increases the binding affinity for Kir2.1 by 5 orders of magnitude (Kd = 0.7 nM). This potent blocker of Kir2.1 may serve as a structural template from which potent compounds for the treatment of various diseases mediated by this channel subfamily, such as cardiac arrhythmia, can be developed

Double-Walled Carbon Nanotubes as Nanosyringes

Functionalized nanoparticles and nanotubes may be able to target specific cells, become ingested and then release their contents in response to a chemical trigger. An alternative delivery mechanism, which may offer advantages in drug delivery is the use of a nanosyringe which pierces the cell membrane and injects molecules such as DNA or anticancer drugs directly into the cell. Here, we propose the use of double-walled carbon nanotubes as nanosyringes. By way of illustration we investigate the suction and expulsion mechanisms, using elementary mechanics and applied mathematical modeling techniques, for both a C60 fullerene and the anticancer drug cisplatin, but similar calculations can be undertaken for any molecule. Some specific guidelines are formulated to assist medical scientists to facilitate nanosyringe development