蒙特卡洛模拟退火与距离限制相结合的方法在多肽溶液构象分析中的应用

多维核磁共振技术的飞速发展议得其在生物大分子结构测定方面的应用已经达到可以与【射线晶体学并驾齐驱的地步．蛋白质结构堆积紧密，较适合于用核磁共振方法给出确定的结构．与蛋白质不同的是多肽的柔性较大，在溶液中可能存在多种构象，核磁共振实验给出的只是平均信息＊．利用核磁，（振数据构建分子结构模型常用的方法有距离几何、分子动力学等，在由核磁共振NOESZ得到的距离信息足够多时可以给出较好的结果问．由于多肽本身的特点：柔性较大，由核磁共振得到的距离信息较少等，利用距离几何、分子动力学方法进行构象搜索时容易陷入…     

高分子链的柔性及其与结构的关系

长链高分子的柔性赋于高分子材料一系列特殊性能,因此研究高分子链的柔性程度及其与高分子链结构和性能的关系,有着极为重要的基础意义,在讨论和研究高分子链柔性时,必须分清静态柔性和动态柔性。静态柔性指的是热力学平衡态柔性,它反映在溶液内高分子的构象和形态,而动态柔性是指在外界条件的影响下从一种平衡态构象转变成另一种平衡态构象的速度过程。本文的讨论仅限于高分子链的静态柔性。     

原卟啉原IX的构象分析

在合理药物设计方法中 ,当靶标酶的三维结构未知时 ,对其底物进行构象分析 ,特别是确定其活性构象 ,对阐明靶标酶活性中心的空间形状和作用位点具有十分重要的意义。我们曾利用距离比较法确定了原卟啉原氧化酶的底物—原卟啉原IX的活性构象 ,本文从构象分析的角度对 4种不同构象的原卟啉原IX分子与二苯醚类分子的晶体学构象进行了几何参数的比较和分析 ,结果进一步证实了距离比较法所确定的活性构象更为可靠     

原卟啉原Ⅸ的构象分析

在合理药物设计方法中,当靶标酶的三维结构未知时,对其底物进行构象分析,特别是确定其活性构象,对阐明靶标酶活性中心的空间形状和作用位点具有十分重要的意义.我们曾利用距离比较法确定了原卟啉原氧化酶的底物-原卟啉原Ⅸ的活性构象,本文从构象分析的角度对4种不同构象的原卟啉原Ⅸ分子与二苯醚类分子的晶体学构象进行了几何参数的比较和分析,结果进一步证实了距离比较法所确定的活性构象更为可靠.     

基于几何约束的蛋白质-配体准确结合自由能计算

蛋白质-配体的结合过程伴随着复杂的结构变化, 在分子模拟可及的时间尺度内难以完全捕获, 这使得准确估计蛋白质-配体的结合自由能十分困难. 一种有效的解决途径是采用几何约束减小需要采样的构象空间, 再通过后处理方式扣除约束的影响. 本文综述了三种几何约束策略——漏斗状约束、球形约束和七自由度约束与自由能计算算法结合准确计算结合自由能的原理和进展, 重点概述理论严谨的七自由度约束的最新进展以及与Alchemistry或重要性采样方法的联用策略, 最后, 讨论了如何针对不同体系选择合适的计算策略以及蛋白质-配体准确结合自由能计算在药物设计等领域中的挑战和前景, 并提出了将上述方法进一步运用于研究更复杂的蛋白质-蛋白质问题的可能性.     

联吡啶构象异构的理论研究

采用HF/6-31G*方法,对6种联吡啶构造异构体进行了构象分析.之后采用B3LYP/6-311G**方法对处于势能面上的能量极小构象异构体进行全自由度几何优化和频率分析,并且寻找构象异构化过渡态.采用自洽反应场极化导体模型溶剂理论,探讨了水溶剂对优势构象异构体的几何结构和能量的影响.     

模拟退火方法研究线性肽构象与环化的关系

采用蒙特卡罗模拟退火方法对一系列线性五肽进行了构象分析，探索了线性肽的优势构象与其环化产率之间的关系．构象分析所得到的预测结果与实验结果吻合．     

简化的系统搜索法及其在构象分析中的应用

多肽的构象研究除了可以用X-射线晶体学及二维核磁共振等实验方法外,理论计算的方法有系统搜索法、蒙特卡洛方法、距离几何方法、分子动力学方法及能量极小化等.系统搜索法具有构象空间搜索彻底的特点,相对来说找到系统整体极小值的可能性较大,但由于其计算量较大,对于多肽及蛋白质很难实现.我们对系统搜索法进行了简化,不是同时旋转所有的二面角,而是成对地进行,以迭代的方法达到收敛,最后得到可能的构象.     

α-丙氨酸构象的理论计算

用Hyperchem软件中的构象搜寻模块,对Od-丙氨酸进行系统构象搜索,寻找分子低能构象．用B3LYP／6—311＋＋G（d,p）法优化计算13个低能构象,PCM（Polarizable Continuum Models）用于水相计算,获得低能构象的优化几何结构、分子总能量和标准吉布斯自由能．较详细地讨论了α-丙氨酸各构象的相对稳定性,水的溶剂化作用对其能量、几何构型和偶极距的影响等问题．此外,还探讨了一水合丙氨酸的几何构型和能量性质．     

Abinitio方法研究2，4－二甲基－1，3－戊二烯结构

用ａｂｉｎｉｔｉｏ方法研究２，４－二甲基－１，３－戊二烯各种构象异构体的结构，找到ｓ－ｔｒａｎｓ和ｓ－ｃｉｓ两种稳定构象，且ｓ－ｔｒａｎｓ更稳定．对稳定构象的几何结构、电荷分布进行了研究，讨论了不同的电子基组对优化几何的影响，并计算了稳定构象的热力学常数，与实验结果进行了比较．     

Protein structure prediction aided by geometrical and probabilistic constraints

Database-assisted ab initio protein structure prediction methods have exhibited considerable promise in the recent past, with several implementations being successful in community-wide experiments (CASP). We have employed combinatorial optimization techniques toward solving the protein structure prediction problem. A Monte Carlo minimization algorithm has been employed on a constrained search space to identify minimum energy configurations. The search space is constrained by using radius of gyration cutoffs, the loop backbone dihedral probability distributions, and various secondary structure packing conformations. Simulations have been carried out on several sequences and 1000 conformations have been initially generated. Of these, 50 best candidates have then been selected as probable conformations. The search for the optimum has been simplified by incorporating various geometrical constraints on secondary structural elements using distance restraint potential functions. The advantages of the reported methodology are its simplicity, and modifiability to include other geometric and probabilistic restraints.     

Copolymerization of Ethylene with 1,9‐Decadiene: Part II—Prediction of Molecular Weight Distributions

In the present work, adaptive orthogonal collocation and a Monte Carlo method are used to compute the molecular weight distributions (MWD) of ethylene/1,9‐decadiene copolymers produced with a constrained geometry catalyst. Predictions from each model are compared to each other and to the experimental MWDs, allowing for the evaluation of relative strengths and weaknesses of each mathematical modeling method. Comparisons with experimental results indicate that the rate of macromonomer incorporation in the growing polymer chains decays with the macromonomer radius of gyration. In all cases, the proposed models are able to fit appropriately the available experimental MWDs.     

Intermolecular hydrogen bonds in hetero-complexes of biologically active aromatic ligands: Monte Carlo simulations results

We report results of the Monte Carlo simulations of systems containing heterodimers of biological active ligands and water molecules. The study was designed to identify the possible formation of intermolecular hydrogen bonds in such systems in order to investigate the molecular mechanisms of hetero-association of aromatic ligands in aqueous solution. The geometry optimization and the calculation of the atomic charges of free ligands were carried out at DFT/B3LYP level of theory. Monte Carlo simulations with Metropolis algorithm were used to determine the low energy conformations of heterodimers in water clusters. The analysis of the Monte Carlo simulation results allows us to describe in detail the hydration properties of all investigated heterodimers and to determine the intermolecular hydrogen bonds between the functional donor–acceptor groups for some of hetero-associates under investigation. In the case of heterodimers without intermolecular hydrogen bonds, the additional stabilization of these hetero-complexes can be explained by the formation the water bridges between donor and acceptor groups of the ligands.     

Collapse transitions of a supersized neutral chain due to irreversibly adsorbed small colloidal particles

 We performed Monte Carlo simulations to study the destabilization processes of large neutral and flexible polymer chains due to irreversibly adsorbed colloidal particles attached to the chains like beads on a necklace. The particles are modeled as charged spherical units which interact with each other via repulsive electrostatic and attractive van der Waals (vdW) potentials. The usual Monte Carlo search procedure is extended and carefully checked to completely sample the chain conformational space and achieve dense conformations in the limit of both strong attractive and repulsive interaction potentials. Configurational properties, such as the radius of gyration, the end-to-end length, and the Kuhn length, are calculated as a function of the intensity of the vdW interactions and ionic strength values. It is observed that chains exhibit a new range of possible conformations compared to the classical random walk and self avoiding walk chains or polyelectrolytes. In the limit of low salt concentration, by gradually increasing vdW interactions, chains undergo a cascade of transitions from extended structures to dumbbells, from dumbbells to pearl necklaces, and from pearl necklaces to collapsed coils. Because of strong competition between the vdW and electrostatic forces, the distance along the chain between the interacting particles, and the sampling limitations, these transitions are found to sample metastable domains and to depend on the initial conformations. To gain insight into the spatial organization of the collapsed conformations, the pair correlation functions of both monomers and particles are calculated. It is shown that collapsed conformations which are the result of strong particle–particle interactions exhibit two distinct parts: a hard core mainly composed of particles and a surrounding polymeric shell composed of loops and tails. Possible effects of such a collapsed transition on the kinetics of flocculation of a mixture containing large flexible chains and small adsorbing colloidal particles are discussed. Received: 26 July 1999 Accepted in revised form: 9 November 1999     

Monte Carlo calculations on polypeptide chains. VIII. Distribution functions for the end-to-end distance and radius of gyration for hard-sphere models of randomly coiling poly(glycine) and poly(L-alanine).

A Monte Carlo study of the distribution functions for the end-to-end distance and radius of gyration for hard-sphere models of poly(glycine) and poly(L-alanine) random coils has been conducted in the chain-length range n = 3 to 100 monomer units for both unperturbed chains and chains perturbed by long-range interactions (excluded volume effects). The distribution functions for the radius of gyration in all cases have been very precisely calculated, those for the perturbed end-to-end distance less precisely, and those for the unperturbed end-to-end distance least precisely. Empirical distribution functions of the form W(p) = ap-b exp(-cp-d) for the reduced end-to-end distance p = r/"r-2"-one-half and a similar form for the reduced radius of gyration could be least-squares fit to the Monte Carlo data. The expansion factors alpha-r and alpha-s were calculated vs. chain length and were used to test various versions of the two-parameter theory of the excluded volume effect. To be consistent with the chain-length dependence of alpha-r and alpha-s as determined by the Monte Carlo calculations, each of these theories required two different binary cluster integrals, a beta-r based on alpha-r and a beta-s based on alpha-s, both of which were strongly chain-length dependent. Both of these results suggest that the two-parameter theory is not applicable to the models used in this study. It was also found that, except for very short chain lengths, plots of ln alphs-r vs. ln n were linear, and thus that alpha-r could be estimated for long chain lengths. Comparison of these estimates with the experimental data on four polypeptide chains in one-earth solvents that the hard-sphere models used in this study yield expansion factors that do not seriously overestimate the magnitude of the excluded volume effect.     

A QXP-based multistep docking procedure for accurate prediction of protein-ligand complexes

The two great challenges of the docking process are the prediction of ligand poses in a protein binding site and the scoring of the docked poses. Ligands that are composed of extended chains in their molecular structure display the most difficulties, predominantly because of the torsional flexibility. On the basis of the molecular docking program QXP-Flo+0802, we have developed a procedure particularly for ligands with a high degree of rotational freedom that allows the accurate prediction of the orientation and conformation of ligands in protein binding sites. Starting from an initial full Monte Carlo docking experiment, this was achieved by performing a series of successive multistep docking runs using a local Monte Carlo search with a restricted rotational angle, by which the conformational search space is limited. The method was established by using a highly flexible acetylcholinesterase inhibitor and has been applied to a number of challenging protein-ligand complexes known from the literature.     

Studies on the behavior of nanoconfined homopolymers with cyclic chain architecture

We have performed Monte Carlo simulations to study the effect of cyclic architecture on the behavior of homopolymer chains under several conditions of confinement. The collapse of the rings in two stages, a coil-to-globule and a liquidlike-to-solidlike transition, was observed even at extreme confinement. Both transitions were observed at lower temperatures than for linear chains of the same length, 2%-5% lower for unconfined systems, and 10%-15% lower for wall separations below three bond lengths due to the effect of confinement. When the plates separation approached the two-dimensional regime, the coil-to-globule transition shifted to lower temperatures. The inverse trend was observed when the chain length was increased. In the collapsed state, the average size and conformations of linear and cyclic molecules of same length were similar independently of confinement. At temperatures near the coil-to-globule transition, the radius of gyration of unconfined linear chains, [R(g)(2)](linear), became larger than for the cyclic chains, [R(g)(2)](cyclic), and this difference increased considerably with confinement. The radius of gyration ratio [R(g)(2)](linear)/[R(g)(2)](cyclic) in this region decreased rapidly. The decrease was more pronounced and occurred at lower temperatures for slit width confinements. At higher temperatures, in the coil state, the radius of gyration ratio became nearly constant for a given separation, and varied from 0.56 for unconfined systems to 0.47 when the chain was completely confined between the walls. This reduction was attributed to the higher increase in the average size of linear chains with confinement when compared with cyclic chains, due to architectural restrictions.     

Computer simulations of polymer chain structure and dynamics on a hypersphere in four-space

There is a rapidly growing interest in performing computer simulations in a closed space, avoiding periodic boundary conditions. To extend the range of potential systems to include also macromolecules, we describe an algorithm for computer simulations of polymer chain molecules on S3, a hypersphere in four dimensions. In particular, we show how to generate initial conformations with a bond angle distribution given by the persistence length of the chain and how to calculate the bending forces for a molecule moving on S3. Furthermore, we discuss how to describe the shape of a macromolecule on S3, by deriving the radius of gyration tensor in this non-Euclidean space. The results from both Monte Carlo and Brownian dynamics simulations in the infinite dilution limit show that the results on S3 and in R3 coincide, both with respect to the size and shape as well as for the diffusion coefficient. All data on S3 can also be described by master curves by suitable scaling by the corresponding values in R3. We thus show how to extend the use of spherical boundary conditions, which are most effective for calculating electrostatic forces, to polymer chain molecules, making it possible to perform simulations on S3 also for polyelectrolyte systems.     

Conformational analysis of siloxane-based enzyme-mimic precursors[1]

The conformational flexibility of six hybrid organodisiloxane oligomers were studied using the Low Mode-Monte Carlo conformational search method with the MM2* force field and the Generalized Born/Surface Area continuum solvent model for water. These systems have enzyme-like properties as synthetic acyltransferases and contain aminopyridine groups in various states of protonation. An ensemble of low energy structures was generated and used to investigate the dependence of molecular shape and flexibility on protonation, which plays an important role in catalyst solubility and self-association. The results as measured by the number of unique conformations, end-to-end or longest intramolecular distance and radius of gyration of the conformational point cloud indicate that the number of protonated pyridines plays a significant role in the overall molecular shape. A similar study was also carried out on various POSS-substitutive organodisiloxane oligomers.