Three parallel algorithms for classical molecular dynamics are presented. The first assigns each processor a fixed subset of atoms; the second assigns each a fixed subset of inter-atomic forces to compute; the third assigns each a fixed spatial region. The algorithms are suitable for molecular dynamics models which can be difficult to parallelize efficiently—those with short-range forces where the neighbors of each atom change rapidly. They can be implemented on any distributed-memory parallel machine which allows for message-passing of data between independently executing processors. The algorithms are tested on a standard Lennard-Jones benchmark problem for system sizes ranging from 500 to 100,000,000 atoms on several parallel supercomputers--the nCUBE 2, Intel iPSC/860 and Paragon, and Cray T3D. Comparing the results to the fastest reported vectorized Cray Y-MP and C90 algorithm shows that the current generation of parallel machines is competitive with conventional vector supercomputers even for small problems. For large problems, the spatial algorithm achieves parallel efficiencies of 90% and a 1840-node Intel Paragon performs up to 165 faster than a single Cray C9O processor. Trade-offs between the three algorithms and guidelines for adapting them to more complex molecular dynamics simulations are also discussed.

Fast parallel algorithms for short-range molecular dynamics

4907 A great deal of interest has surrounded the use of monoclonal antibodies (mAbs) for the selective delivery of cytotoxic agents to tumor cells. We have previously demonstrated that mAb-auristatin conjugates are highly active, leading to cures and regressions of established tumors in nude mice. These antibody-drug conjugates (ADCs) contain a dipeptide valine-citrulline-p-aminobenzylcarbamate (vc-PABC) linker used to join the antimitotic drugs monomethylauristatin E or F (MMAE, MMAF) to a series of antitumor mAbs. This linker was selected for plasma stability and cleavage by lysosomal enzymes such as cathepsin B. Here, we describe several other dipeptide sequences, many of which are not cathepsin B substrates, for the attachment of auristatins to mAb carriers. More than 20 mAb-dipeptide-PABC-MMAF ADCs were prepared, all of which were active in vitro and in vivo independent of peptide sequence. There was no apparent improvement over the vc-PABC linker, since the PABC group facilitated lysosomal drug release. In contrast, a new series of mAb-MMAF conjugates was prepared in which the dipeptide linkers were directly attached to the C-terminal phenylalanine on the drug without using an intervening PABC spacer. Many of the dipeptide sequences contained unnatural amino acids in order to increase the stringency of drug release. Peptide sequences were identified within the new conjugates that led to both greater tolerability and higher potency compared to corresponding vc-PABC ADCs. The new linkers play an important role in ADC activity and tolerability, and mAb-auristatin conjugates derived from them are candidates for future development.

Novel peptide linkers for highly potent antibody-auristatin conjugates

Cell-penetrating peptide: a means of breaking through the physiological barriers of different tissues and organs

Nearly one in six people worldwide suffer from disorders of the central nervous system (CNS). There is an urgent need for effective strategies to improve the success rates in CNS drug discovery and development. The lack of effective technologies for delivering drugs and genes to the brain due to the blood-brain barrier (BBB), a structural barrier that effectively blocks most neurotherapeutic agents from reaching the brain, has posed a formidable hurdle for CNS drug development. Brain-homing and brain-penetrating molecular transport vectors, such as brain permeable peptides or BBB shuttle peptides, have shown promise in overcoming the BBB and ferrying the drug molecules to the brain. The BBB shuttle peptides are discovered by phage display technology or derived from natural neurotropic proteins or certain viruses and harness the receptor-mediated transcytosis molecular machinery for crossing the BBB. Brain permeable peptide-drug conjugates (PDCs), composed of BBB shuttle peptides, linkers, and drug molecules, have emerged as a promising CNS drug delivery system by taking advantage of the endogenous transcytosis mechanism and tricking the brain into allowing these bioactive molecules to pass the BBB. Here, we examine the latest development of brain-penetrating peptide shuttles and brain-permeable PDCs as molecular vectors to deliver small molecule drug payloads across the BBB to reach brain parenchyma. Emerging knowledge of the contribution of the peptides and their specific receptors expressed on the brain endothelial cells, choice of drug payloads, the design of PDCs, brain entry mechanisms, and delivery efficiency to the brain are highlighted. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.

Brain penetrating peptides and peptide–drug conjugates to overcome the blood–brain barrier and target CNS diseases

Smart nano-carriers have attained great significance in the biomedical field due to their versatile and interesting designs with different functionalities. The initial stages of the development of nanocarriers mainly focused on the guest loading efficiency, biocompatibility of the host and the circulation time. Later the requirements of less side effects with more efficacy arose by attributing targetability and stimuli-responsive characteristics to nano-carriers along with their bio- compatibility. Researchers are utilizing many stimuli-responsive polymers for the better release of the guest molecules at the targeted sites. Among these, pH-triggered release achieves increasing importance because of the pH variation in different organ and cancer cells of acidic pH. This specific feature is utilized to release the guest molecules more precisely in the targeted site by designing polymers having specific functionality with the pH dependent morphology change characteristics. In this review, we mainly concert on the pH-responsive polypeptides and some interesting nano-carrier designs for the effective theranostic applications. Also, emphasis is made on pharmaceutical application of the different nano-carriers with respect to the organ, tissue and cellular level pH environment.

https://www.mdpi.com/1420-3049/24/16/2961/pdf

pH-Responsive Polypeptide-Based Smart Nano-Carriers for Theranostic Applications

Complementary to endocytosis, cell-penetrating peptides (CPPs) at high concentrations can penetrate the cell membrane in a direct way, which further makes CPPs popular candidates for delivering therapeutic or diagnostic agents. Although featured as rapid uptake, the translocation efficiency and potential toxicity of the direct penetration are usually affected by cargoes, which is still unclear. Here, using coarse-grained molecular dynamics simulations, we show that the polyarginine (R8) peptides penetrate the membrane through a water pore in the membrane, and the transmembrane efficiency is improved by conjugating to small nanoparticles (NPs) with proper linkers. It can be attributed to both the extension of the lifetime of the water pore by the NPs and outward diffusion of negative lipids in the asymmetry membrane, which induces the surrounding R8-NP conjugates to the water pore before it is closed. The translocation efficiency is closely related to the length of the linkers, and it gets the maximum value when the length of the linkers is around half of the membrane thickness. Overlong linkers not only decrease the transmembrane efficiency because of the blockage of NPs in the water pore but may also cause cytotoxicity because of the unclosed water pore. The results provide insights into the internalization of CPPs and facilitate the design of CPP and drug conjugates with high efficiency and low toxicity.

Improved Intracellular Delivery of Polyarginine Peptides with Cargoes.

The display bandwidth and display mechanism determine the performance of the three-dimensional (3D) display system. In this paper, a bandwidth-enhanced depth priority integral imaging (DPII) technique is proposed. Information transmission efficiency (ITE) defined as the output display bandwidth divided by the input display bandwidth is used to assess the II system. By analyzing the ITE, we find that only a part of the input display bandwidth is used efficiently to present the 3D image in the traditional DPII system. The DPII system sacrifices the ITE for depth enhancement. The low ITE that fundamentally limits the 3D performance of the DPII system is ascribed to the diffusing illumination mechanism of the display system. To enhance the 3D performance, a collimated illumination DPII system as a special case of band-limited diffusing illumination technique has been proposed and demonstrated first. The bandwidth and ITE of such a DPII system are increased. The depth of field (DOF) of the system is doubled. The resolution of the 3D image is increased to the level of the resolution priority II system without sacrificing the viewing angle. A more general case, band-limited illumination DPII system is also demonstrated. By modulating the divergence angle of the illumination system, the 3D image’s resolution and DOF can be controlled. The bandwidth and ITE of the DPII system using band-limited illumination are also higher than that of the traditional DPII system. Experiments are presented to prove the bandwidth-enhanced mechanism of the DPII system.

Bandwidth-enhanced depth priority integral imaging using a band-limited diffusing illumination technique.

Design and fabrication of ultrathin lighting responsive security device based on moiré imaging phenomenon

A method to enhance the performance of an integral imaging system is demonstrated using the time-multiplexed convergent backlight technique. The backlight increases the space bandwidth of the integral imaging system. As a result, the resolution, depth of field, and viewing angle of the integral imaging system are increased simultaneously. The cross-talk noise is also decreased without using any optical barrier. One part of the added space bandwidth comes from the optimized illumination. The other part is converted from the time bandwidth of the system by time-multiplexing. The time-multiplexed convergent backlight modulates the direction of the backlight in time sequence to illuminate the elemental images. Then, the elemental images synthesize the 3D images using a microlens array. An elemental images rendering method using a conjugate pinhole camera and pinhole projector model is designed to dynamically match the illumination direction. The rendering method eliminates the distortion and maximizes the viewing angle and viewing zone. A field programmable gate array (FPGA)-based controller is used to manage and synchronize the time sequence of the backlight and the display devices. Using this technique, high-performance 3D images are realized. Comparison experiments of the integral imaging system using diffused backlight and convergent backlight are performed. The results show the effectiveness of the proposed technique.

Enhancing integral imaging performance using time-multiplexed convergent backlight.

The imaging principles and phenomena of integral imaging technique have been studied in detail using geometrical optics, wave optics, or light filed theory. However, most of the conclusions are only suit for the integral imaging systems using diffused illumination. In this work, a kind of twin imaging phenomenon and mechanism has been observed in a non-diffused illumination reflective integral imaging system. Interactive twin images including a real and a virtual 3D image of one object can be activated in the system. The imaging phenomenon is similar to the conjugate imaging effect of hologram, but it base on the refraction and reflection instead of diffraction. The imaging characteristics and mechanisms different from traditional integral imaging are deduced analytically. Thin film integral imaging systems with 80μm thickness have also been made to verify the imaging phenomenon. Vivid lighting interactive twin 3D images have been realized using a light-emitting diode (LED) light source. When the LED is moving, the twin 3D images are moving synchronously. This interesting phenomenon shows a good application prospect in interactive 3D display, argument reality, and security authentication.

Wu Fengmin

Papers

Improved Intracellular Delivery of Polyarginine Peptides with Cargoes.

Bandwidth-enhanced depth priority integral imaging using a band-limited diffusing illumination technique.

Design and fabrication of ultrathin lighting responsive security device based on moiré imaging phenomenon

Enhancing integral imaging performance using time-multiplexed convergent backlight.

Twin imaging phenomenon of integral imaging