蛋白质-蛋白质分子对接中打分函数研究进展

分子对接是研究分子间相互作用与识别的有效方法.其中,用于近天然构象挑选的打分函数的合理设计对于对接中复合物结构的成功预测至关重要.本文回顾了蛋白质-蛋白质分子对接组合打分函数中一些主要打分项,包括几何互补项、界面接触面积、范德华相互作用能、静电相互作用能以及统计成对偏好势等打分项的计算方法.结合本研究小组的工作,介绍了目前普遍使用的打分方案以及利用与结合位点有关的信息进行结构筛选的几种策略,比较并总结了常用打分函数的特点.最后,分析并指出了当前蛋白质-蛋白质对接打分函数所存在的主要问题,并对未来的工作进行了展望.     

从接触电荷转移复合物的光谱测定化合物的电离势

分子氧可以作为电子受体与很多有机化合物形成接触电荷转移复合物(CCT),从而在长波处产生新的具有最大吸收峰的CCT光谱。本文采用比较法测定了醚类、醇类,胺类、烃类等三十多种有机化合物的CCT光谱。推导了从CCT光谱计算有机化合物电离势的经验公式,并由此计算了上述三十多种有机化合物的电离势。     

确定蛋白质-短肽复合物结构的新方法

大部分蛋白质 -蛋白质复合物的三维结构在接触表面都显示出很好的几何匹配 .由于蛋白质的表面几何形状和其它的一些物理化学性质在分子的专一性相互作用中起了主要作用 ,所以 ,接触表面几何形状的互补常常被认为是蛋白质分子识别的基础 .一般来说 ,蛋白质接触表面的几何匹配只涉及 5到 1 0几个紧密堆积的氨基酸残基 ,因此 ,蛋白质与蛋白质配体之间的识别计算可以通过蛋白质与突变周围的或与蛋白质表面紧密接触的配体肽段的识别计算来实现 . Stoddard等 [1] 已经利用从 MBP上选取的八肽成功地计算出接近晶体结构的 MBP-受体复合物 .许多研…     

原子Schrǒdinger方程直接求解的相关函数-势谐-广义Laguerre函数方法

引入相关函数,将势谐-广义Laguerre函数(PHGLF)方法发展为相关函数-势谐-广义Laguerre函数(CFPHGLF)方法,应用于He,H~-,Li~+和Be~(2+)等三体体系的n~1S(n=1～4)态.得到了比由PHGLF方法更精确的激发态n~1S(n=2～4)本征能量,且从n=2至4,与Hylleraas组态相互作用(HCI)能量愈来愈近,如He原子的3个激发态的本征能与最精确的HCI之差分别为0.001 827,0.000 666,0.000 376(a. u.);但基态的能量本征值逊于PHGLF方法.结果表明,非势谐函数对基态波函数尚有较显著的贡献,对激发态波函数的贡献较小;在势谐方案下,对基态(1~1S)应考虑电子间的相关,对于激发态重要的是消除电子与核间的歧点.     

14种结合自由能评价函数的比较

采用LigandFit作为构象采样工具，以230个蛋白质-配体复合物组成的预测集，系统地比较了14种自由能评价函数（Ligscore1、Ligscore2、Plp1、Plp2、Jain、Pmf、Ludi1、Ludi2、Ludi3、D-score、Pmf-score、G-score、Chemscore以及Xscore）对蛋白质和小分子之间的结合模式以及结合自由能的预测能力. Plp1、Plp2、G-score、Pmf和Xscore在预测测试集结合自由能时得到的分数同实验测定的结合自由能的线性相关系数大于50%. 在识别配体分子实验结合构象的能力方面， 选择测试构象与实际构象间的位置均方根偏差rmsd≤0.20 nm作为评价标准，14种评价函数的成功率从46%到77%不等，其中Ligscore1、Ligscore2、Plp1、Plp2以及Xscore的成功率都在70%以上. 将评价函数中的2个或者3个组合得到一组共同评价函数可以进一步提高实验构象的预测能力， 其预测成功率可以达到80%. 实验表明Xscore、Plp1和Plp2在对接和评价方面都得到较好的结果.     

Application of Extended-Rydberg Parameters for Extracting the 2-Body Portion of Kaxiras–Pandey Function

A set of relationship is developed herein between parameters of the Extended-Rydberg and the 2-body portion of the Kaxiras–Pandey potential energy functions. Unlike previous method which relied on multi-derivatives, the approach herein adopts the series expansion approach in order to recast the 2-body part of the Kaxiras–Pandey potential into a form similar to the Extended-Rydberg function. Results plotted for eight pairs of diatoms reveal good correlation. The improved agreement, as evident from a narrower gap between two sets of potential functions, may well be attributed to the removal of simplifying assumptions that were invoked in the previous method. The present relationship, together with other recently developed parametric relations, will be used for the development of an interatomic potential function converter.     

Porous Protein Crystals as Catalytic Vessels for Organometallic Complexes

Porous protein crystals, which are protein assemblies in the solid state, have been engineered to form catalytic vessels by the incorporation of organometallic complexes. Ruthenium complexes in cross‐linked porous hen egg white lysozyme (HEWL) crystals catalyzed the enantioselective hydrogen‐transfer reduction of acetophenone derivatives. The crystals accelerated the catalytic reaction and gave different enantiomers based on the crystal form (tetragonal or orthorhombic). This method represents a new approach for the construction of bioinorganic catalysts from protein crystals.     

基态N2O－的势能函数研究

以6-311＋＋G(3df, 3pd)为基函数, 采用密度泛函理论的B3LYP方法对N₂O^－分子体系的结构进行了优化计算. 结果表明N₂O^－分子最稳态为C_s构型, 电子组态为²A', 平衡核间距R_N—N＝0.11873 nm, R_N—O＝0.13012 nm, 键角∠NNO＝133.94448°, 离解能D_e＝10.3857 eV, 基态简正振动频率: 弯曲振动频率ν₁＝656.7488 cm^－1, 对称伸缩振动频率ν₂＝998.1562 cm^－1, 反对称伸缩振动频率ν₃＝1684.3093 cm^－1. 并用多体展式理论方法推导出了基态N₂O^－分子的分析势能函数, 其等值势能图准确地再现了N₂O^－分子的结构特征和离解能.     

PuN和PuN_2基态分子的结构与势能函数

用相对论有效原子实势和密度泛函理论方法对PuN和PuN_2分子的结构进行优化 ，得到了其平衡几何构型和谐振频率。采用最小二乘法拟合出PuN基态分子的 Murrell-Sorbie解析势能函数，在此基础上推导出光谱数据和力常数，并用多体展 式理论导出PuN_2基态分子的解析势能函数，正确地反映了其平衡构型特性。     

Impressive Enrichment of Semiempirical Quantum Mechanics-Based Scoring Function: HSP90 Protein with 4541 Inhibitors and Decoys

This paper describes the excellent performance of a newly developed scoring function (SF), based on the semiempirical QM (SQM) PM6-D3H4X method combined with the conductor-like screening implicit solvent model (COSMO). The SQM/COSMO, Amber/GB and nine widely used SFs have been evaluated in terms of ranking power on the HSP90 protein with 72 biologically active compounds and 4469 structurally similar decoys. Among conventional SFs, the highest early and overall enrichment measured by EF₁ and AUC% obtained using single-scoring-function ranking has been found for Glide SP and Gold-ASP SFs, respectively (7, 75 % and 3, 76 %). The performance of other standard SFs has not been satisfactory, mostly even decreasing below random values. The SQM/COSMO SF, where P−L structures were optimised at the advanced Amber level, has resulted in a dramatic enrichment increase (47, 98 %), almost reaching the best possible receiver operator characteristic (ROC) curve. The best SQM frame thus inserts about seven times more active compounds into the selected dataset than the best standard SF.     

Ab Initio Ground-State Potential Energy Function and Vibration-Rotation Energy Levels of Aluminum Monohydride

The accurate ground-state potential energy function of aluminum monohydride (AlH) has been determined from ab initio calculations using the multireference averaged coupled-pair functional (MR-ACPF) method in conjunction with the correlation-consistent core-valence basis sets up to septuple-zeta quality. The vibration-rotation energy levels of the two isotopologues, AlH and AlD, were predicted to near the “spectroscopic” accuracy. The importance of electron correlation beyond the MR-ACPF level of approximation, the scalar relativistic, spin-orbit, adiabatic, and nonadiabatic effects was discussed. © 2019 Wiley Periodicals, Inc.     

Scaling for Experimental Inner-Sphere Reorganization Energy of Hydrated Ions via Accurate Potential Function

Reported here are several new calculation methods for the inner-sphere reorganization energy of hydrated metal ions involved in electron transfer processes.It is based on the self-exchange model of reorganization and utilizes the more exact potential functions between central metal ion and the inner-sphere ligands.The parameters involved are determined via the spectroscopic and thermodynamic data.The predictions of the inner-sphere reorganization energies from those models agree well with the photoemission experimental results.     

Protein Labelling with Versatile Phosphorescent Metal Complexes for Live Cell Luminescence Imaging

To take advantage of the luminescent properties of d⁶ transition metal complexes to label proteins, versatile bifunctional ligands were prepared. Ligands that contain a 1,2,3‐triazole heterocycle were synthesised using Cu^I catalysed azide–alkyne cycloaddition “click” chemistry and were used to form phosphorescent Ir^III and Ru^II complexes. Their emission properties were readily tuned, by changing either the metal ion or the co‐ligands. The complexes were tethered to the metalloprotein transferrin using several conjugation strategies. The Ir^III/Ru^II–protein conjugates could be visualised in cancer cells using live cell imaging for extended periods without significant photobleaching. These versatile phosphorescent protein‐labelling agents could be widely applied to other proteins and biomolecules and are useful alternatives to conventional organic fluorophores for several applications.