基于结构的O-GlcNAc转移酶抑制剂的虚拟筛选

利用O-GlcNAc 转移酶同UDP-GlcNAc复合物的晶体结构,针对其催化位点,对ZINC库中的7134792个分子和FOG库中的4287550个分子进行三轮(HTVS、SP、XP)虚拟筛选,结果发现具有更好类药性的FOG库中包含更多对接得分更低的小分子,且具有更多新颖的化学片段.ZINC库中具有较低对接得分的分子可分为2类,分别占据UDP-GlcNAc的UDP和GlcNAc的结合位置,在此基础上设计得到的分子具有更好的对接得分.证明FOG分子库具有产生更多对接得分更低的分子,所预测和设计的小分子化合物可以成为潜在的抑制剂药物分子.     

Fluctuation effects on microphase separation in random copolymers

Summary We study random copolymers consisting of two kinds of monomers with attraction between similar kinds. The mean-field analysis of this system indicates a continuous phase transition into a phase with periodic microdomain structure. It is shown that the inverse of the renormalized propagator has a minimum at non-zero wave numbers. Consequently, there is an anomalously large contribution of fluctuations that make the disordered phase locally stable. However, below a certain temperature, the ordered phase is shown to be locally stable and a weak first-order transition is possible, with qualitative differences from the weak crystallization theory developed by Brazovskii. These differences are due to the peculiar form of the fourth-order vertex of the effective Hamiltonian for the system. We calculated the temperature region for the validity of the mean-field estimates of the amplitude and the scale of microphase separation. Paper presented at the I International Conference on Scaling Concepts and Complex Fluids, Copanello, Italy, July 4–8, 1994.     

4,9-Dihydrobenz[f]indole-4,9-dione derivatives synthesis and properties of 2,3,4,9-tetrahydrobenz[f]indole-2,4,9-triones and 2,3,4,9-tetrahydrobenz[f]indole-2,3,4,9-tetrones

Under the influence of amines, (3-chloro-1,4-naphthoquinon-2-yl)malonic ester is cyclized to 3-carbethoxy derivatives of 2,3,4,9-tetrahydrobenz[f]indole-2,4,9-trione, which were decarboxylated and then oxidized to 2,3,4,9-tetrahydrobenz[f]indole-2,3,4,9-tetrone derivatives. Methylation of 2,3,4,9-tetrahydrobenz[f]indole-2,4,9-triones leads to a mixture of O- and C-methyl derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 911–914, July, 1976.     

Structural determinant of protein designability

Here we present an approximate analytical theory for the relationship between a protein structure's contact matrix and the shape of its energy spectrum in amino acid sequence space. We demonstrate a dependence of the number of sequences of low energy in a structure on the eigenvalues of the structure's contact matrix, and then use a Monte Carlo simulation to test the applicability of this analytical result to cubic lattice proteins. We find that the lattice structures with the most low-energy sequences are the same as those predicted by the theory. We argue that, given sufficiently strict requirements for foldability, these structures are the most designable, and we propose a simple means to test whether the results in this paper hold true for real proteins.     

原子吸收和电感耦合等离子体发射光谱法测定某些重要的埃及植物

本文讨论了用原子吸收和电感耦合等离子体发射光谱法（ＩＣＰ－ＡＥＳ）测定经高压釜溶解的营养性埃及植物，如胡芦巴、甘草和莲座丛，并讨论了该法用于被消解植物样品中多元素日常分析的优点。这些样品具有较宽的元素含量范围，准确地测定这些营养性样品的主量和微量元素特别是有毒元素，对埃及人民的健康非常重要。ＩＣＰ－ＡＥＳ法同时也用于被视为尼罗河净化剂的水生风信子的分析。分析结果表明，该植物能够有效地吸收有毒元素。被研究的植物经高压釜溶解，其溶液经原子吸收和ＩＣＰ－ＡＥＳ法测定。作者对分析结果进行了对比，并阐明了二者之间的关系。     

Sequence correlations shape protein promiscuity

We predict analytically that diagonal correlations of amino acid positions within protein sequences statistically enhance protein propensity for nonspecific binding. We use the term "promiscuity" to describe such nonspecific binding. Diagonal correlations represent statistically significant repeats of sequence patterns where amino acids of the same type are clustered together. The predicted effect is qualitatively robust with respect to the form of the microscopic interaction potentials and the average amino acid composition. Our analytical results provide an explanation for the enhanced diagonal correlations observed in hubs of eukaryotic organismal proteomes [J. Mol. Biol. 409, 439 (2011)]. We suggest experiments that will allow direct testing of the predicted effect.     

Diversity Against Adversity: How Adaptive Immune System Evolves Potent Antibodies

Adaptive immunity is an amazing mechanism, whereby new protein functions—affinity of antibodies (Immunoglobulins) to new antigens—evolve through mutation and selection in a matter of a few days. Despite numerous experimental studies, the fundamental physical principles underlying immune response are still poorly understood. In considerable departure from past approaches, here, we propose a microscopic multiscale model of adaptive immune response, which consists of three essential players: The host cells, viruses, and B-cells in Germinal Centers (GC). Each moiety carries a genome, which encodes proteins whose stability and interactions are determined from their sequences using laws of Statistical Mechanics, providing an exact relationship between genomic sequences and strength of interactions between pathogens and antibodies and antibodies and host proteins (autoimmunity). We find that evolution of potent antibodies (the process known as Affinity Maturation (AM)) is a delicate balancing act, which has to reconcile the conflicting requirements of protein stability, lack of autoimmunity, and high affinity of antibodies to incoming antigens. This becomes possible only when antibody producing B cells elevate their mutation rates (process known as Somatic Hypermutation (SHM)) to fall into a certain range—not too low to find potency increasing mutations but not too high to destroy stable Immunoglobulins and/or already achieved affinity. Potent antibodies develop through clonal expansion of initial B cells expressing marginally potent antibodies followed by their subsequent affinity maturation through mutation and selection. As a result, in each GC the population of mature potent Immunoglobulins is monoclonal being ancestors of a single cell from initial (germline) pool. We developed a simple analytical theory, which provides further rationale to our findings. The model and theory reveal the molecular factors that determine the efficiency of affinity maturation, thereby providing insight into the variability of the immune response to cytopathic viruses (the direct response by germline antibodies) and poorly cytopathic viruses (a crucial role of SHM in the response).