计算机辅助糖苷酶分子设计与改造研究进展

糖苷酶作为一种重要的生物催化剂,在工业生物催化领域有着广阔的应用前景.但天然糖苷酶存在催化活性低、热稳定性和底物选择性差等缺点,严重限制了它在规模化生产中的推广应用.近年,有关糖苷酶催化机制与结构功能关系的研究备受关注,特别是计算机辅助酶设计在相关研究领域发挥着越来越重要的作用.我们综述了糖苷酶分子设计改造过程中应用的计算机辅助方法:包括同源比对、分子对接以及动力学模拟;阐述了这些计算方法在糖苷酶的结构与功能关系解析、酶催化分子机制、酶催化性能改造方面的应用现状.最后,对开发智能精准的计算分析方法的新发展趋势进行了展望.     

含双核铁中心金属蛋白和金属酶的研究进展

介绍了三种含双核铁活性中心的金属蛋白和金属酶的最新研究进展，它们是蚯蚓血红蛋白，甲烷单加氧酶，核糖核苷酸还原酶。     

金属离子对金属蛋白结构与功能的调控

生命金属在生命过程中以不同的化学方式发挥着重要的作用。质膜、细胞器膜等使不同的生命金属在生物体系中有着不同的隔室化分布,相应的金属蛋白或金属伴侣蛋白在维持金属离子内稳态(homeostasis)中起着关键作用。生命体系中广泛存在着具有两个以上金属离子结合部位的金属蛋白。在确定的生理微环境下,由于金属离子结合热力学性质的不等价,该类金属蛋白的生物学功能取决于所结合金属离子的种类及多少。本文以伴刀豆球蛋白A、铜/锌超氧化物歧化酶、中心蛋白、锌指蛋白为例,介绍了金属离子在调控金属蛋白生物学功能中的作用。因此,深入研究金属离子与金属蛋白结合的热力学性质对于理解生命过程的无机化学基础具有重要意义。     

计算机辅助合成设计的基本原理

近年来，国际上在计算机辅助有机合成设计的理论与实践方面日臻完善，对此，国内也已有文章介绍在本文中，作者将根据自己研制计算机辅助合成设计系统的实践，从基本原理和技术路线的角度来介绍这项研究工作的细节，期望能够抛砖引玉，使更多化学界同行了解计算机辅助化学设计的前景与进展，并加入研究的行列。     

遗传算法在计算机辅助药物分子设计中的应用

作为一种重要的启发式优化算法,遗传算法在计算机辅助药物分子设计中得到了广泛的应用.本文介绍了遗传算法的基本概念以及工作原理,同时结合作者科研组的工作,就遗传算法在定量构效关系、构象分析、药效团模拟、分子对接以及虚拟组合化学等方面的应用做了系统的阐述。     

萃取溶剂选择的计算机辅助分子设计中的数学方法

萃取精馏是分离沸点相近或具有恒沸组成混合物的一种重要方法。选择最优的萃取剂是提高生产能力和降低能耗的根本途径。萃取剂选择的计算机辅助分子设计（CAMD）是基于性质估算的方法即通过CAMD来生成一组具有期望性质的分子,然后再对候选分子进行筛选。目前,CAMD法的研究主要可分为生成一验证、数学优化和组合优化。生成一验证法通常使用启发式的策略,是基于知识的,无法克服基团的组合爆炸问题,也不能保证结果的最优性;数学优化方法,包括混合整数非线性规划（MINLP）和混合整数线性规划（MILP）,可用于表达非线性或线性的结构．性质关系,但准确表达结构-性质关系还有困难;组合优化法是使用遗传算法或模拟退火算法、禁忌搜索等的方法,理论上可克服以上问题。本文评述了以上三种方法在萃取精馏溶剂选择领域中的用途、原理及其工业化所面临的主要问题。     

计算机图象识别辅助菌种筛选及对甾体激素微生物酶反应的研究

将分形理论和计算机图象纹理分析技术移植到微生物发酵研究中，对菌落和菌丝本形态的定量描述了探讨，并利用菌种的分维特征作为筛选高产菌株的直观指标，有效地提高了菌种筛选工作的效率与准确度，探讨了沃氏底物霉菌转化的工艺过程，并以生物全息观念与分形理论为依托，在分形尺度上对生物体形态及其发育过程进行了描述，建立起菌体生长的形态动力学模型，并与生长（浓度）动力学模型相结合，设计出可判别理论最佳投料点的酶活描述     

计算机辅助有机合成路线设计系统LHASA

计算机辅助有机合成路线设计系统ＬＨＡＳＡ洪汇孝，忻新泉（南京大学化学系２１０００８）ＬＨＡＳＡ（ＬｏｇｉｃａｎｄＨｅｕｒｉｓｔｉｃｓＡｐｐｌｉｅｄｔｏＳｙｎｔｈｅｔｉｃＡｎａｌｙｓｉｓ）［１－４］是一个交互式计算机辅助有机合成路线设计软件。该软件于６...     

计算机辅助药物设计中的多维定量构效关系模型化方法

多维定量构效关系(MD QSAR)在计算机辅助药物设计中得到了广泛而成功的应用,结合本研究组的工作,本文系统综述了建立各种MD QSAR模型的方法和策略,对近年来有关的MD QSAR应用研究进展进行了回顾,并对其在新世纪药物设计中应用前景做了展望。     

蛋白质分子理性设计与肌红蛋白功能的调控及拓展

蛋白质分子理性设计,不但对于揭示天然金属蛋白的结构与功能关系,而且对于创造具有性质和功能改善的人工金属蛋白,都是一个功能强大的策略.肌红蛋白(myoglobin,Mb),自然界创造的一种具有多重生物功能的血红素蛋白,已被证明是蛋白质分子理性设计的理想框架.本文主要综述了两个方面,一是对其天然的氧结合与运输、过氧化物酶(peroxidase)和亚硝酸盐还原酶(nitrite reductase,NIR)的功能进行调控,二是将其功能理性拓展到过氧酶(peroxygenase)、血红素-铜氧化酶(heme-copper oxidase,HCO)、一氧化氮还原酶(nitric oxide reductase,NOR)和羟胺还原酶(hydroxylamine reductase)等.这些研究加深了我们对自然界金属蛋白如何工作的理解,也为将来具有实际应用前景的功能金属蛋白的理性分子设计提供了线索.     

Selective formation of AAB- and ABC-type heterotrimeric alpha-helical coiled coils

The alpha-helical coiled coils have a representative amino acid sequence of (abcdefg)(n) heptad repeats. We previously reported that two peptides named IZ-2A and IZ-2W formed an (IZ-2A)(2)/IZ-2W heterotrimer with an Ala-Ala-Trp interaction in the hydrophobic core. In this paper, we describe the selective formation of AAB- and ABC-type heterotrimers. To increase the selectivity of the AAB-type heterotrimeric formation, Lys residues at the f position were mutated to either an Ala or a Gln residue to form IZ-2A(fA) or IZ-2W(fQ). Separately, both IZ-2A(fA) and IZ-2W(fQ) have a random structure at pH 7 and 20 degrees C. However, together IZ-2A(fA) and IZ-2W(fQ) form a 2:1 complex with a thermal transition midpoint (Tm) of 48 degrees C. This procedure was applied to prepare the ABC-type heterotrimer, in which two sets of Ala-Ala-Trp interactions were designed in the hydrophobic core. Interhelical interaction between the e and g positions and the alpha-helical propensity of the amino acid at the f position were also considered in the design. The resultant three peptides selectively formed the ABC-type heterotrimer with a Tm of 51 degrees C. Other peptide combinations had random coil properties.     

蛋白质全新设计：八残基序列形成发夹结构的圆二色谱

β-发夹是天然蛋白质中丰富的二级结构单元之一，在蛋白折叠和功能方面扮演着重要角色.文章报导了二条多肽序列（LTVd-PGLTV，n7和 LTVGDDTV， n5）的设计、合成和园二色谱研究结果.结果显示，n5在198 nm附近呈现负峰，表现为非规整结构特征；相反，n7表现为典型的发夹结构特征，在218 nm附近呈负峰,196 nm附近呈正峰，为β-转角与β-折叠的共同贡献.初步研究表明，β-转角、序列关系和氨基酸形成β-折叠结构倾向性是β-发夹结构形成和稳定的决定性因素.     

Combinatorial docking and combinatorial chemistry: Design of potent non-peptide thrombin inhibitors

A computational algorithm was used to design automatically novel thrombin inhibitors that are available from a single-step chemical reaction. The compounds do not contain amide bonds, are achiral and have a molecular weight below 400. Of the 10 compounds that were synthesized, five bind to thrombin with a Ki in the nanomolar range. Subsequent X-ray structure determination of the thrombin-inhibitor complex for the best compound (Ki=95 nM) confirms the predicted binding mode. The novel algorithm is applicable to a broad range of chemical reactions.     

β-发夹多肽的全新设计和构象研究

引入跨股氨基酸队的方法进行β-发夹结构的设计,序列[R1G2T3F4W5V6d-p7S8V9N10Y11F12,β2]中包含二个氨基酸对V6V9和F4Y11,并以d-p7S8作转角来稳定结构.多肽合成采用Fmoc/Bu4固相合成方法.圆二色谱研究显示,β2在202 nm呈现正峰,在217.5 nm处呈负峰,为β转角和β折叠共同贡献的叠加,是典型的β-发夹结构圆二色谱特征.红外光谱研究进一步验证了圆二色谱的结果,表明β2在溶液中主要以β-发夹结构存在.     

Prediction of folding stability and degradability of thede novo designed protein MB-1 in cow rumen

The authors have recently reported on the design of a protein (MB-1) enriched in methionine, threonine, lysine, and leucine. The protein is intended to be produced by rumen bacteria, in a way that would provide high producing lactating cows with limiting amino acids. In this report, MB-1 stability in the rumen is assessed, i.e., where the protein might be found after cell lysis or after being secreted by rumen bacteria. Current in vitro methods used to predict proteolytic degradability in the rumen were used for MB-1, as well as other natural proteins for comparison. MB-1 was found to be more susceptible to degradation than cytochrome c and ribonuclease A. Data indicate that MB-1 will be rapidly degraded if exposed to the rumen environment without protection. The contribution of folding stability to proteolytic stability was also examined. Rumen liquor components were selected to formulate a solution compatible with constraints of thermal denaturation studies. Denaturation curves show that the natural proteins were folded at rumen temperature. The MB-1 denaturation curves indicated that MB-1 does not unfold in a cooperative transition when heated from 20 to 70‡C. This suggests that MB-1 structure may be progressively modified as temperature increases, and that a continuum of conformations are available to MB-1. At 39‡C, a significant (50%) portion of MB-1 molecules had their tertiary structure unfolded, contributing to proteolytic degradability. Despite the unusual constraints used in MB-1 design (i.e., a maximized content in selected essential amino acids), results show that MB-1 has structural properties similar to previously reportedde novo designed proteins.     

A Consensus Compound/Bioactivity Dataset for Data-Driven Drug Design and Chemogenomics

Publicly available compound and bioactivity databases provide an essential basis for data-driven applications in life-science research and drug design. By analyzing several bioactivity repositories, we discovered differences in compound and target coverage advocating the combined use of data from multiple sources. Using data from ChEMBL, PubChem, IUPHAR/BPS, BindingDB, and Probes & Drugs, we assembled a consensus dataset focusing on small molecules with bioactivity on human macromolecular targets. This allowed an improved coverage of compound space and targets, and an automated comparison and curation of structural and bioactivity data to reveal potentially erroneous entries and increase confidence. The consensus dataset comprised of more than 1.1 million compounds with over 10.9 million bioactivity data points with annotations on assay type and bioactivity confidence, providing a useful ensemble for computational applications in drug design and chemogenomics.