Computational structural determination and energy landscape analysis of the hepatic carcinogen 2-(acetylamino)fluorene

 2-(Acetylamino)fluorene (AAF), a potent mutagen and a prototypical example of the mutagenic aromatic amines, forms covalent adducts to DNA after metabolic activation in the liver. A benchmark study of AAF is presented using a number of the most widely used molecular mechanics and semiempirical computational methods and models. The results are compared to higher-level quantum calculations and to experimentally obtained crystal structures. Hydrogen bonding between AAF molecules in the crystal phase complicates the direct comparison of gas-phase theoretical calculations with experiment, so Hartree–Fock (HF) and Becke–Perdew (BP) density functional theory (DFT) calculations are used as benchmarks for the semiempirical and molecular mechanics results. Systematic conformer searches and dihedral energy landscapes were carried out for AAF using the SYBYL and MMFF94 molecular mechanics force fields; the AM1, PM3 and MNDO semiempirical quantum mechanics methods; HF using the 3-21G*and 6-31G* basis sets; and DFT using the nonlocal BP functional and double numerical polarization basis sets. MMFF94, AM1, HF and DFT calculations all predict the same planar structures, whereas SYBYL, MNDO and PM3 all predict various nonplanar geometries. The AM1 energy landscape is in substantial agreement with HF and DFT predictions; MMFF94 is qualitatively similar to HF and DFT; and the MNDO, PM3 and SYBYL results are qualitatively different from the HF and DFT results and from each other. These results are attributed to deficiencies in MNDO, PM3 and SYBYL. The MNDO, PM3 and SYBYL models may be unreliable for compounds in which an amide group is immediately adjacent to an aromatic ring. Received: 26 May 2002 / Accepted: 12 December 2002 / Published online: 14 February 2003     

QuanPol: A full spectrum and seamless QM/MM program

The quantum chemistry polarizable force field program (QuanPol) is implemented to perform combined quantum mechanical and molecular mechanical (QM/MM) calculations with induced dipole polarizable force fields and induced surface charge continuum solvation models. The QM methods include Hartree–Fock method, density functional theory method (DFT), generalized valence bond theory method, multiconfiguration self‐consistent field method, Møller–Plesset perturbation theory method, and time‐dependent DFT method. The induced dipoles of the MM atoms and the induced surface charges of the continuum solvation model are self‐consistently and variationally determined together with the QM wavefunction. The MM force field methods can be user specified, or a standard force field such as MMFF94, Chemistry at Harvard Molecular Mechanics (CHARMM), Assisted Model Building with Energy Refinement (AMBER), and Optimized Potentials for Liquid Simulations‐All Atom (OPLS‐AA). Analytic gradients for all of these methods are implemented so geometry optimization and molecular dynamics (MD) simulation can be performed. MD free energy perturbation and umbrella sampling methods are also implemented. © 2013 Wiley Periodicals, Inc.     

DommiMOE: an implementation of ligand field molecular mechanics in the molecular operating environment

The ligand field molecular mechanics (LFMM) model, which incorporates the ligand field stabilization energy (LFSE) directly into the potential energy expression of molecular mechanics (MM), has been implemented in the "chemically aware" molecular operating environment (MOE) software package. The new program, christened DommiMOE, is derived from our original in-house code that has been linked to MOE via its applications programming interface and a number of other routines written in MOE's native scientific vector language (SVL). DommiMOE automates the assignment of atom types and their associated parameters and popular force fields available in MOE such as MMFF94, AMBER, and CHARMM can be easily extended to provide a transition metal simulation capability. Some of the unique features of the LFMM are illustrated using MMFF94 and some simple [MCl)]2- and [Ni(NH3)n]2+ species. These studies also demonstrate how density functional theory calculations, especially on experimentally inaccessible systems, provide important data for designing improved LFMM parameters. DommiMOE treats Jahn-Teller distortions automatically, and can compute the relative energies of different spin states for Ni(II) complexes using a single set of LFMM parameters.     

A Robust and Cost-Efficient Scheme for Accurate Conformational Energies of Organic Molecules

Several standard semiempirical methods as well as the MMFF94 force field approximation have been tested in reproducing 8 DLPNO-CCSD(T)/cc-pVTZ level conformational energies and spatial structures for 37 organic molecules representing pharmaceuticals, drugs, catalysts, synthetic precursors, industry-related chemicals (37conf8 database). All contemporary semiempirical methods surpass their standard counterparts resulting in more reliable conformational energies and spatial structures, even though at significantly higher computational costs. However, even these methods show unexpected failures in reproducing energy differences between several conformers of the crown ether 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6). Inexpensive force field MMFF94 approximation groups with contemporary semiempirical methods in reproducing the correct order of conformational energies and spatial structures, although the performance in predicting absolute conformational energies compares to standard semiempirical methods. Based on these findings, we suggest a two-step strategy for reliable yet feasible conformational search and sampling in realistic-size flexible organic molecules: i) geometry optimization/preselection of relevant conformers using the MMFF94 force field; ii) single-point energy evaluations using a contemporary semiempirical method. We expect that developed database 37conf8 is going to be useful for development of semiempirical methods.     

Structure of cis-[Pt(NH_3)(2-picoline)]~(2+) and DNA adduct and its bonding characteristics

Several methods including molecular mechanics, molecular dynamics, ONIOM that combines quantum chemistry with molecular mechanics and standard quantum chemistry are used to study the configuration and electron structures of an adduct of the DMA segment d(ATACATG*G*TACATA)-d(TATGTACCATGTAT) with cis-[Pt(NH3)(2-Picoline)]2+. The investigation shows that the configuration optimized by ONIOM is similar to that determined by NMR. Strong chemical bonds between Pt of the complex and two N7s of neighboring guanines in the DNA duplex and hydrogen bond between the NH3of the complex and O6 of a nearby guanine have a large impact on the configuration of the adduct. Chemical bonds, the aforementioned hydrogen bond, and the interaction between a methyl of the complex and a methyl of the base in close proximity are critical for the complex to specifically recognize DNA.     

A sobering assessment of small‐molecule force field methods for low energy conformer predictions

We have carried out a large scale computational investigation to assess the utility of common small‐molecule force fields for computational screening of low energy conformers of typical organic molecules. Using statistical analyses on the energies and relative rankings of up to 250 diverse conformers of 700 different molecular structures, we find that energies from widely used classical force fields (MMFF94, UFF, and GAFF) show unconditionally poor energy and rank correlation with semiempirical (PM7) and Kohn–Sham density functional theory (DFT) energies calculated at PM7 and DFT optimized geometries. In contrast, semiempirical PM7 calculations show significantly better correlation with DFT calculations and generally better geometries. With these results, we make recommendations to more reliably carry out conformer screening.     

分子间弱相互作用的计算——构建氢键、卤键势能面

介绍一个面向大三下学期本科生的计算化学实验。通过量子化学计算对比研究两种分子间弱相互作用——氢键和卤键的势能面,使学生对势能面的概念及两种弱相互作用的区别有一定的直观认识。通过实际上机操作,初步了解Gaussian、Gaussview及Origin等计算化学相关软件的使用,并深入理解结构化学及计算化学课程中所学的理论知识。     

分子力场进展

分子力学（简称ＭＭ）是近年来化学家常用的一种计算方法。与量子力学从头计算和半经验方法相比，用分子力学处理大分子可以大大节省计算时间，而且，在大多数情况下，用分子力学方法计算得到的分子几何构型参数与实验值之间的差值可在实验误差范围之内。所以，分子力学是研究生物化学体系的有效和可行的手段。分子力学的核心是分子力场。本文介绍了分子力场的量子力学背景、分子力场和光谱力场之间的关系。分子力场的一般形式、分力     

经典价键理论的从头算计算方法

价键理论是两大现代化学键理论之一,广泛应用于化学键本质和化学反应机理的研究。由于计算困难,价键理论应用局限于定性的讨论而无法有效地开展从头计算研究。现代经典价键理论在经典价键理论的理论基础上,引入合理有效的计算方法,提高了价键计算的效率。本文回顾近年来经典价键理论从头算方法在提高计算精度和拓展研究范围方面的发展,并简要展望价键理论方法的发展趋势。     

Conformational analysis and rotational barriers of alkyl- and phenyl-substituted urea derivatives

Potential energy surfaces (PES) for rotation about the N-C(sp(3)) or N-C(aryl) bond and energies of stationary points on PES for rotation about the C(sp(2))-N bond are reported for methylurea, ethylurea, isopropylurea, tert-butylurea, and phenylurea, using the B3LYP/DZVP2 and MP2/aug-cc-pVDZ methods. The analysis of alkylureas reveals cis and (less stable) trans isomers that adopt anti geometries, whereas syn geometries do not correspond to stationary points. In contrast, the analysis of phenylurea reveals that the lowest energy form at the MP2 level is a trans isomer in a syn geometry. The fully optimized geometries are in good agreement with crystal structure data, and PESs are consistent with the experimental dihedral angle distribution. Rotation about the C(sp(2))-N bond in alkylureas and phenylurea is slightly more hindered (8.6-9.4 kcal/mol) than the analogous motion in the unsubstituted molecule (8.2 kcal/mol). At the MP2 level of theory, the maximum barriers to rotation for the methyl, ethyl, isopropyl, tert-butyl, and phenyl groups are predicted to be 0.9, 6.2, 6.0, 4.6, and 2.4 kcal/mol, respectively. The results are used to benchmark the performance of the MMFF94 force field. Systematic discrepancies between MMFF94 and MP2 results were improved by modification of several torsional parameters.     

Structure of <Emphasis Type="Italic">cis</Emphasis>-[Pt(NH<Subscript>3</Subscript>)(2-picoline)]<Superscript>2+</Superscript> and DNA adduct and its bonding characteristics

Several methods including molecular mechanics, molecular dynamics, ONIOM that combines quantum chemistry with molecular mechanics and standard quantum chemistry are used to study the configuration and electron structures of an adduct of the DNA segment d(ATACATG*G*TACATA)d(TATGTACCATGTAT) with cis-[Pt(NH₃)(2-Picoline)]²⁺. The investigation shows that the configuration optimized by ONIOM is similar to that determined by NMR. Strong chemical bonds between Pt of the complex and two N7s of neighboring guanines in the DNA duplex and hydrogen bond between the NH₃of the complex and O6 of a nearby guanine have a large impact on the configuration of the adduct. Chemical bonds, the aforementioned hydrogen bond, and the interaction between a methyl of the complex and a methyl of the base in close proximity are critical for the complex to specifically recognize DNA.     

Consensus bond-charge increments fitted to electrostatic potential or field of many compounds: Application to MMFF94 training set

Bond-charge increments (BCIs) are additive parameters used to assign atomic charges for the MMFF force field. BCI parameters are classified parsimoniously according to two atom types and the bond order. We show how BCIs may be fitted rapidly by linear least squares to the calculated ab initio electrostatic potential (ESP) or to the electrostatic field. When applied simultaneously to a set of compounds or conformations, the method yields consensus values of the BCIs. The method can also derive conventional “ESP-fit” atomic charges with improved numerical stability. The method may be generalized to determine atom multipoles, multicenter charge templates, or electronegativities, but not polarizability or hardness. We determine 65 potential-derived (PD) BCI parameters, which are classified as in MMFF, by fitting the 6-31G* ESP or the electrostatic field of the 45 compounds in the original MMFF94 training set. We compare the consensus BCIs with classified BCIs that were fit to each molecule individually and with “unique-bond” BCIs (ESP-derived atom charges). Consensus BCIs give a satisfactory representation for about half of the structures and are robust to the adjustment of the alkyl CH bond increment to the zero value employed in MMFF94. We highlight problems at three levels: Point approximation: the potential near lone pairs on sulfur and to some extent nitrogen cannot be represented just by atom charges. Bond classification: BCIs classified according to MMFF atom types cannot represent all delocalized electronic effects. The problem is especially severe for bonds between atoms of equivalent MMFF type, whose BCI must be taken as zero. Consensus: discrepancies that occur in forming the consensus across the training set indicate the need for a more detailed classification of BCIs. Contradictions are seen (e.g., between acetic acid and acetone and between guanidine and formaldehydeimine). We then test the three sets of PD-BCIs in energy minimizations of hydrogen-bonded dimers. Unique-bond BCIs used with the MMFF buffered 14–7 potential reproduce unscaled quantum chemical dimer interaction energies within 0.9 kcal/mol root mean square (or 0.5, omitting two N-oxides). These energies are on average 0.7 (or 0.5) kcal/mol too weak to reproduce the scaled quantum mechanical (SQM) results that are a benchmark for MMFF parameterization. Consensus BCIs tend to weaken the dimer energy by a further 0.4–0.6 kcal/mol. Thus, consensus PD-BCIs can serve as a starting point for MMFF parameterization, but they require both systematic and individual adjustments. Used with a “harder” AMBER-like Lennard–Jones potential, unique-bond PD-BCIs without systematic adjustment give dimer energies in fairly good agreement with SQM. ©1999 John Wiley & Sons, Inc. J Comput Chem 20: 1495–1516, 1999     

原子电荷计算方法的对比

原子电荷是对化学体系中电荷分布最简单、最直观的描述形式之一,在理论和实际应用中都有重要意义.本文介绍了12种重要的原子电荷计算方法的原理和特点,通过大量实例从不同角度比较了它们的优缺点.这些方法包括Mulliken、分子环境中的原子轨道(AOIM)、Hirshfeld、原子偶极矩校正的Hirshfeld布居(ADCH)、自然布居分析(NPA)、Merz-Kollmann(MK)、分子中的原子(AIM)、Merck分子力场94(MMFF94)、AM1-BCC、Gasteiger、电荷模型2(CM2)以及电荷均衡(QEq)方法.最后本文对如何在实际应用中选择合适的计算方法给出了建议.     

Shapes of sulfur, oxygen, and nitrogen mustards

Thorough conformational analyses have been performed on representative sulfur, oxygen, and nitrogen mustards. A total of 23, 18, and 38 unique conformers have been located for SM, OM, and NM, respectively, at the MP2/aug-cc-pVDZ level of theory. Despite the fact that these molecules differ only in the identity of the central heteroatom, comparison of their low energy conformations reveals that the shapes they adopt are distinctive to each molecule. Potential energy surfaces for CH(2)-X (X = S, O, and N-CH(3)) and CH(2)-CH(2) bond rotations are presented and, where possible, compared with dihedral angle distributions observed in crystal structure data. These results were used to benchmark and improve the performance of the MM3 and MMFF94 force fields.     

A Classical and Quantum Chemical Analysis of Gaseous Heat Capacity

Physical chemistry is considered to be a scientifically abstract and mathematically intensive course in the undergraduate chemistry curriculum. To most students, the physical chemistry course involves a semester that deals with macroscopic properties and another that deals with microscopic evaluations of chemical systems. They often fail to see the importance of statistical mechanics in making the connection between the content of the two semesters. In this paper, we propose a computational exercise that complements a simple physical chemistry experiment that can be used to understand the chemical basis of a macroscopic property such as the heat capacity of gases using microscopic (classical and quantum) mechanics. Students are given the opportunity to use (1) computational chemistry software to calculate the contributions of translational, rotational, and vibrational motion to the energy of molecules; (2) a graphing program to study the linear and nonlinear dependence of energy on temperature; (3) classical, quantum, and statistical mechanical theory to verify experimental data; (4) regression analysis to approximate the heat capacity constant of simple gases from energy calculations.     

Simulation of intramolecular hydrogen bond dynamics in manzamine A as a sensitive test for charge distribution quality

Subtle balance of inter- and intramolecular hydrogen bond strength in aqueous solutions often governs the structure and dynamics of molecular species used as potential drugs and in supramolecular applications. In silico molecular dynamics study of water solution of manzamine A has been performed with different atomic charges in order to investigate the influence of charge distribution choice on predicting qualitative and quantitative features of the simulated systems. Various well known charge schemes (MK-ESP, RESP, Mulliken, AMI-BCC, Gasteiger-Hückel, Gasteiger-Marsili, MMFF94, and Dynamic Electronegativity Relaxation - DENR) led to qualitatively different pictures of dynamic behavior of the intramolecular hydrogen bond. The reported calculation framework represents a relatively rare case where differences in charge distributions lead to noticeable differences in simulated properties, thus providing a useful test case for force field and charge distribution development, provided high quality experiments are conducted to use as references.     

Electronic Structure and Circular Dichroism of Natural Alboatisins Isolated from Aerial Parts of Isodon Albopilosus: DFT and TDDFT Study

The stable conformations of a series of bioactive molecules, (?)-alboatisins A?C, are identified via Monte Carlo searching with the MMFF94 molecular mechanics force field. Then, the optical rotation (OR) values, vibrational circular dichroism (VCD), and electronic circular dichroism (ECD) spectra were calculated using the gradient-corrected density functional theory method. The vibrational and transition modes of molecular chirality were explored in terms of their microscopic origin. The calculated specific rotations are in agreement with the experimental values. From the OR analysis, it was concluded that optical rotation values areregulated by hydroxyl substitution. Vibrations occurring on the chiral skeleton may cause strong absorption in VCD spectra; VCD spectra are thus the spectral response to deformation vibrations on the chiral carbon skeleton. The lowest-energy negative Cotton effect is caused by σ→π^* transition. Frontier molecular orbital analysis showed that strong ECD absorptions are produced when the dominant transition on the chiral skeleton is asymmetric; ECD spectra show the result of transitions lacking asymmetry on the chiral skeleton.     

An Update on Molecularly Imprinted Polymer Design through a Computational Approach to Produce Molecular Recognition Material with Enhanced Analytical Performance

Molecularly imprinted polymer (MIP) computational design is expected to become a routine technique prior to synthesis to produce polymers with high affinity and selectivity towards target molecules. Furthermore, using these simulations reduces the cost of optimizing polymerization composition. There are several computational methods used in MIP fabrication and each requires a comprehensive study in order to select a process with results that are most similar to properties exhibited by polymers synthesized through laboratory experiments. Until now, no review has linked computational strategies with experimental results, which are needed to determine the method that is most appropriate for use in designing MIP with high molecular recognition. This review will present an update of the computational approaches started from 2016 until now on quantum mechanics, molecular mechanics and molecular dynamics that have been widely used. It will also discuss the linear correlation between computational results and the polymer performance tests through laboratory experiments to examine to what extent these methods can be relied upon to obtain polymers with high molecular recognition. Based on the literature search, density functional theory (DFT) with various hybrid functions and basis sets is most often used as a theoretical method to provide a shorter MIP manufacturing process as well as good analytical performance as recognition material.