Molecular modeling optimization of anticoagulant pyridine derivatives

Intravascular clotting remains a major health problem in the United States, the most prominent being deep vein thrombosis, pulmonary embolism and thromboembolic stroke. Previous reports on the use of pyridine derivatives in cardiovascular drug development encourage us to pursue new types of compounds based on a pyridine scaffold. Eleven pyridine derivatives (oximes, semicarbazones, N-oxides) previously synthesized in our laboratories were tested as anticoagulants on pooled normal plasma using the prothrombin time (PT) protocol. The best anticoagulant within the oxime series was compound AF4, within the oxime N-oxide series was compound AF4-N-oxide, and within the semicarbazone series, compound MD1-30Y. We also used a molecular modeling approach to guide our efforts, and found that there was good correlation between coagulation data and computational energy scores. Molecular docking was performed to target the active site of thrombin with the DOCK v5.2 package. The results of molecular modeling indicate that improvement in anticoagulant activities can be expected by functionalization at the three-position of the pyridine ring and by N-oxide formation. Results reported here prove the suitability of DOCK in the lead optimization process.     

Unravel four hairpins!

DNA machines consisting of consecutive hairpins, which we have previously described, have various potential applications in DNA computation. In the present study, a 288-base DNA machine containing four consecutive hairpins was successfully constructed by ligation and PCR. PAGE and fluorescence spectroscopy experiments verified that all four hairpins were successfully opened by four opener oligomers, and that hairpin opening was dependent on the proper openers added in the correct order. Quantitative analysis of the final results by fluorescence spectroscopy indicated that all four hairpins were open in about 1/4 to 1/3 of the DNA machines.     

Identification of variable coefficients for vibrating systems by boundary control and observation

We consider the identification problem of coefficients for vibrating systems described by a Euler-Bernoulli beam eq~. ation Or a string equation, with one end clamped and with an input exerted on the other end. For the beam equation, the observations are the velocity and the angle velocity at the free end, while for the string equation, the observation is the velocity at the free end. In the framework of well-posed linear system theory, we show that both the density and the flexural rigidity of the beam, and the tension of the string, can be uniquely determined by the observations for all positive times. Moreover, a general constructive method is developed to show that the mass density and the elastic modulus of the string are not determined by the observation.     

Arithmetic computation in the tile assembly model: Addition and multiplication

Formalized study of self-assembly has led to the definition of the tile assembly model [Erik Winfree, Algorithmic self-assembly of DNA, Ph.D. Thesis, Caltech, Pasadena, CA, June 1998; Paul Rothemund, Erik Winfree, The program-size complexity of self-assembled squares, in: ACM Symposium on Theory of Computing, STOC02, Montreal, Quebec, Canada, 2001, pp. 459–468]. Research has identified two issues at the heart of self-assembling systems: the number of steps it takes for an assembly to complete, assuming maximum parallelism, and the minimal number of tiles necessary to assemble a shape. In this paper, I define the notion of a tile assembly system that computes a function, and tackle these issues for systems that compute the sum and product of two numbers. I demonstrate constructions of such systems with optimal Θ(1)$\Theta \left(1\right)$ distinct tile types and prove the assembly time is linear in the size of the input.     

Towards understanding the mechanism of action of the multidrug resistance-linked half-ABC transporter ABCG2: a molecular modeling study

The ATP-binding cassette protein ABCG2 is a member of a broad family of ABC transporters with potential clinical importance as a mediator of multidrug resistance. We carried out a homology and knowledge-based, and mutationally improved molecular modeling study to establish a much needed structural framework for the protein, which could serve as guidance for further genetic, biochemical, and structural analyses. Based on homology with known structures of both full-length and nucleotide-binding domains (NBD) of ABC transporters and structural knowledge of integral membrane proteins, an initial model of ABCG2 was established. Subsequent refinement to conform to the lipophilic index distributions in the transmembrane domain (TMD) and to the results of site-directed mutagenesis experiments led to an improved model. The complete ABCG2 model consists of two identical subunits facing each other in a closed conformation. The dimeric interface in the nucleotide-binding domain (NBD) involves a characteristic nucleotide sandwich and the interface in the TMD consists of the TM helices 1–3 of one subunit and the helices 5 and 6 of the other. The interface between the NBD and the TMD is bridged by the conserved structural motif between TM2 and TM3, the intracellular domain 1 (ICD1), and the terminal β-strand (S6) of the central β-sheet in the NBD. The apparent flexibility of the ICD1 may play a role in transmitting conformational changes from the NBD to the TMD or from the TMD to the NBD.     

基于图论的化学分子数据挖掘研究

近年来,人们提出了很多频繁图模式挖掘的算法。首先分析了贪婪搜索策略,然后对各种不同的图数据挖掘的方法进行比较。受购物篮分析的影响,基于ILP方法引起了人们的重视。如何修改各种不同的图数据挖掘方法以适用化学分子数据的挖掘是人们研究的热点问题。因为化学分子不仅是标准的图结构,而且它有典型的频繁环和链结构,还有一些频繁出现的代表原子类型的结点,所以在这个领域有一些特殊问题需要考虑。     

Influence of particle elasticity in shear testers

Two dimensional simulations of non-cohesive granular matter in a biaxial shear tester are discussed. The effect of particle elasticity on the mechanical behavior is investigated using two complementary distinct element methods (DEM): Soft particle molecular dynamics simulations (Particle Flow Code, PFC) for elastic particles and contact dynamics simulations (CD) for the limit of perfectly rigid particles. As soon as the system dilates to form shear bands, it relaxes the elastic strains so that one finds the same stresses for rigid respectively elastic particles in steady state flow. The principal stresses in steady state flow are determined. They are proportional to each other, giving rise to an effective macroscopic friction coefficient which is about 10% smaller than the microscopic friction coefficient between the grains.     

Molecular Dynamics Simulation for Ultrafine Machining

This article surveys the advances of molecular dynamics (MD) simulation in the research of ultrafine machining and related technologies. Modeling methods, including interatomic potentials and boundary conditions, are addressed. Algorithm strategies for MD simulations are discussed. By applying simulations with Tersoff potential, a case study of the material removal mechanism of the polishing based on coupling vibrations of liquid (PCVL) is presented.     

Nanoindentation and nanomachining characteristics of gold and platinum thin films

Molecular dynamics (MD) simulation and an experimental method were carried out to study the effects of applied load, hold time, and temperature on nanoscratching and nanoindentation of gold and platinum thin films. The simulated results showed that the wear depth of gold decreased as the scratching velocity was increased and the temperature was decreased. The results also indicated that when the simulated nanoindentation of gold film hold time was increased, the plastic indentation depth and the plastic energy both increased. In addition, the experimental results showed that the groove depth for gold films was larger than that of platinum films under the same machining load. The wear depth and the surface roughness of platinum films were larger than those of gold films under the same lateral machining feed. Furthermore, the simulated plastic energy of gold films was compared during nanoindentation test.     

Deep levels in GaInAs grown by molecular beam epitaxy and their concentration reduction with annealing treatment

X-ray diffraction (XRD), current–voltage (IV), capacitance–voltage (CV), deep-level transient Fourier spectroscopy (DLTFS) and isothermal transient spectroscopy (ITS) techniques are used to investigate the thermal annealing behaviour of three deep levels in Ga_0.986In_0.014As heavily doped with Si (6.8 × 10¹⁷ cm⁻³) grown by molecular beam epitaxy (MBE). The thermal annealing was performed at 625 °C, 650 °C, 675 °C, 700 °C and 750 °C for 5 min. XRD study shows good structural quality of the samples and yields an In composition of 1.4%. Two main electron traps are detected by DLTFS and ITS around 280 K, with activation energies of 0.58 eV and 0.57 eV, capture cross sections of 9 × 10⁻¹⁵ cm² and 8.6 × 10⁻¹⁴ cm² and densities of 2.8 × 10¹⁶ cm⁻³ and 9.6 × 10¹⁵ cm⁻³, respectively. They appear overlapped and as a single peak, which divides into two smaller peaks after annealing at 625 °C for 5 min.

Annealing at higher temperatures further reduces the trap concentrations. A secondary electron trap is found at 150 K with an activation energy of 0.274 eV, a capture cross section of 8.64 × 10⁻¹⁵ cm² and a density of 1.38 × 10¹⁵ cm⁻³. The concentration of this trap level is also decreased by thermal annealing.