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We perform large-scale atomistic simulations of a system containing 12 × 106 atoms, comprising an oxygen gas-filled bubble immersed in water, to understand the stability and cavitation induced by ultrasound. First, we propose a method to construct a bubble/water system. For a given bubble radius, the pressure inside the bubble is estimated using the Young–Laplace equation. Then, this pressure is used as a reference for a constant temperature, constant pressure simulation of an oxygen system, enabling us to extract a sphere of oxygen gas and place it into a cavity within an equilibrated water box. This ensures that the Young–Laplace equation is satisfied and the bubble is stable in water. Second, this stable bubble is used for ultrasound-induced cavitation simulations. We demonstrate that under weak ultrasound excitation, the bubble undergoes stable cavitation, revealing various fluid velocity patterns, including the first-order velocity field and microstreaming. These fluid patterns emerge around the bubble on a nanometer scale within a few nanoseconds, a phenomenon challenging to observe experimentally. With stronger ultrasound intensities, the bubble expands significantly and then collapses violently. The gas core of the collapsed bubble, measuring 3–4 nm, exhibits starfish shapes with temperatures around 1500 K and pressures around 6000 bar. The simulation results are compared with those from Rayleigh–Plesset equation modeling, showing good agreement. Our simulations provide insights into the stability and cavitation of nanosized bubbles. [ABSTRACT FROM AUTHOR]

It has been widely accepted that cancer cells are softer than their normal counterparts. This motivates us to propose, as a proof-of-concept, a method for the efficient delivery of therapeutic agents into cancer cells, while normal cells are less affected. The basic idea of this method is to use a water jet generated by the collapse of the bubble under shockwaves to perforate pores in the cell membrane. Given a combination of shockwave and bubble parameters, the cancer membrane is more susceptible to bending, stretching, and perforating than the normal membrane because the bending modulus of the cancer cell membrane is smaller than that of the normal cell membrane. Therefore, the therapeutic agent delivery into cancer cells is easier than in normal cells. Adopting two well-studied models of the normal and cancer membranes, we perform shockwave induced bubble collapse molecular dynamics simulations to investigate the difference in the response of two membranes over a range of shockwave impulse 15–30 mPa s and bubble diameter 4–10 nm. The simulation shows that the presence of bubbles is essential for generating a water jet, which is required for perforation; otherwise, pores are not formed. Given a set of shockwave impulse and bubble parameters, the pore area in the cancer membrane is always larger than that in the normal membrane. However, a too strong shockwave and/or too large bubble results in too fast disruption of membranes, and pore areas are similar between two membrane types. The pore closure time in the cancer membrane is slower than that in the normal membrane. The implications of our results for applications in real cells are discussed in some details. Our simulation may be useful for encouraging future experimental work on novel approaches for cancer treatment. [ABSTRACT FROM AUTHOR]

The brain is strictly protected by the blood brain barrier preventing the crossing of therapeutics to treat brain diseases. The high and low intensity focused ultrasound methods have been used to temporarily open the blood brain barrier, facilitating the transport of drugs. The methods are very promising because the opening is transient, localized, and noninvasive. However, the molecular mechanism of the opening is unknown, and this limits the development and application of these methods. With this in mind, we carry out a molecular dynamics simulation study to understand the interaction of ultrasound with the cell membrane and the tight junction. Our minimal blood brain barrier model is composed of two lipid bilayers, mimicking two portions of neighboring cells, connected together by a tight junction formed by a pair of two cis-dimers of the claudin-5 protein. Using an experimental ultrasound frequency of 50 MHz, simulations show that at low intensities, ultrasound does not impact the structure of the cell membranes and tight junction, implying that the direct interaction of ultrasound with the blood brain barrier is not responsible for the experimentally observed opening. At high intensities, the ultrasound pulls the monolayers of individual cell membrane lipid bilayers apart, creating air compartments inside the bilayers. This reduces the free energy barrier for the translocation of drugs across the lipid bilayer and enhances drug permeability. At very high intensities, the two monolayers are largely separated, resulting in cell damage and implying that the blood brain barrier is primarily opened at the experimentally observed damaged areas. [ABSTRACT FROM AUTHOR]

We develop a molecular nanoscaled model for tubular motors propelled by bubble propulsion. The motor is modeled by a carbon nanotube, and the bubble is represented by a particle interacting with water by a time-dependent potential. Effects of liquid viscosity, fuel concentration, geometry, and size of the tube on the performance of the motor are effectively encoded into two parameters: time scales of the bubble expansion and bubble formation. Our results are qualitatively consistent with experimental data of much larger motors. Simulations suggest that (i) the displacement of the tube is optimized if two time scales are as short as possible, (ii) the compromise between the performance and fuel consumption is achieved if the bubble formation time is shorter than the velocity correlation time of the tube, (iii) the motor efficiency is higher with slow expansion, short formation of the bubble than fast growth but long formation time, and (iv) the tube is propelled by strong forces on the order of mN, reaching high speeds up to ∼60 m/s. Our simulation may be useful for refining and encouraging future experimental work on nanomotors having the size of a few nanometers. The tiny size and high speed motors could have great potential applications in real life. [ABSTRACT FROM AUTHOR]

Focused ultrasound (FUS) has a wide range of medical applications. Nowadays, the diagnostic and therapeutic ultrasound procedures are routinely used; effects of ultrasound on biological systems at the molecular level are, however, not fully understood. Experimental results on the interaction of the cell membrane, a simplest but important system component, with ultrasound are controversial. Molecular dynamics (MD) simulations could provide valuable insights, but there is no single study on the mechanism of the FUS induced structural changes in cell membranes. With this in mind, we develop a simple method to include FUS into a standard MD simulation. Adopting the 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid membrane as a representative model described by the MARTINI coarse-grained force field, and using experimental values of the ultrasound frequency and intensity, we show that the heat and bubble cavitation are not the primary direct mechanisms that cause structural changes in the membrane. The spatial pressure gradients between the focused and free regions and between the parallel and perpendicular directions to the membrane are the origin of the mechanism. These gradients force lipids to move out of the focused region, forming a lipid flow along the membrane diagonal. Lipids in the free region move in the opposite direction due to the conservation of the total momentum. These opposite motions create wrinkles along the membrane diagonal at low FUS intensities and tear up the membrane at high FUS intensities. Once the membrane is torn up, it is not easy to reform. The implication of our findings in the FUS-induced drug delivery is discussed in some detail. [ABSTRACT FROM AUTHOR]

While the COVID-19 pandemic continues to worsen, effective medicines that target the life cycle of SARS-CoV-2 are still under development. As more highly infective and dangerous variants of the coronavirus emerge, the protective power of vaccines will decrease or vanish. Thus, the development of drugs, which are free of drug resistance is direly needed. The aim of this study is to identify allosteric binding modulators from a large compound library to inhibit the binding between the Spike protein of the SARS-CoV-2 virus and human angiotensin-converting enzyme 2 (hACE2). The binding of the Spike protein to hACE2 is the first step of the infection of host cells by the coronavirus. We first built a compound library containing 77 448 antiviral compounds. Molecular docking was then conducted to preliminarily screen compounds which can potently bind to the Spike protein at two allosteric binding sites. Next, molecular dynamics simulations were performed to accurately calculate the binding affinity between the spike protein and an identified compound from docking screening and to investigate whether the compound can interfere with the binding between the Spike protein and hACE2. We successfully identified two possible drug binding sites on the Spike protein and discovered a series of antiviral compounds which can weaken the interaction between the Spike protein and hACE2 receptor through conformational changes of the key Spike residues at the Spike–hACE2 binding interface induced by the binding of the ligand at the allosteric binding site. We also applied our screening protocol to another compound library which consists of 3407 compounds for which the inhibitory activities of Spike/hACE2 binding were measured. Encouragingly, in vitro data supports that the identified compounds can inhibit the Spike–ACE2 binding. Thus, we developed a promising computational protocol to discover allosteric inhibitors of the binding of the Spike protein of SARS-CoV-2 to the hACE2 receptor, and several promising allosteric modulators were discovered. [ABSTRACT FROM AUTHOR]