Electrostatic molecular potentials in hydrogen-bonded systems

A study is made of the modifications of the electrostatic molecular potential brought about by hydrogen bonding both in the hydrogen-bond region itself and in the external regions of the proton-acceptor and proton-donor molecules. Systems up to four successive units in a chain of donor-acceptors are considered. The possibility of obtaining a satisfactory picture of the global potential by a simple superposition of the potentials of the individual units is evaluated.     

A new method for modelling spectator chemical groups in ab initio calculations: effective group potentials

 A new method for an increased numerical efficiency of ab initio calculations is proposed. It is based on the assumption that in most cases chemical properties of functional groups in molecules are mainly controlled by a few electrons. This statement allows one to distinguish between two classes of nuclei and electrons: active and inactive ones. The effective group potential (EGP) method presupposes that the effect of inactive electrons in a functional chemical group can be described by a pseudopotential, in the same way that core electrons are replaced by effective core potentials in atoms. It is shown that EGPs are able to predict chemical and structural features of the active part of a molecule and at a fraction of the ordinary computational cost. The preliminary results reported here concern the determination of EGPs for ammonia, the methyl radical and the cyclopendadienyl ligand, which represent different types of bonding. Received: 15 September 1999 / Accepted: 3 February 2000 / Published online: 2 May 2000     

A comparative study ofab-initio effective core potential and all-electron calculations for molecular structures and transition states

The reliability of theab-initio effective core potential method for calculating molecular geometries was tested for several polyatomic molecules by using the energy gradient technique. The calculated geometries are in good agreement with those of all-electron calculation not only for equilibrium but also for transition states. The heat of reaction and the activation barrier height compare very well with those of all-electron calculation as well.     

MEPSIM: A computational package for analysis and comparison of molecular electrostatic potentials

Summary MEPSIM is a computational system which allows an integrated computation, analysis, and comparison of molecular electrostatic potential (MEP) distributions. It includes several modules. Module MEPPLA supplies MEP values for the points of a grid defined on a plane which is specified by a set of three points. The results of this program can easily be converted into MEP maps using third-parties graphical software. Module MEPMIN allows to find automatically the MEP minima of a molecular system. It supplies the cartesian coordinates of these minima, their values, and all the geometrical relationships between them (distances, angles, and dihedral angles). Module MEPCOMP computes a similarity coefficient between the MEP distributions of two molecules and finds their relative position that maximizes the similarity. Module MEPCONF performs the same process as MEPCOMP, considering not only the relative position of both molecules but also a conformational degree of freedom of one of them. The most recently developed module, MEPPAR, is another modification of MEPCOMP in order to compute the MEP similarity between two molecules, but only taking into account a particular plane. The latter module is particularly useful to compare MEP distributions generated by systems of aromatic rings. MEPSIM can use several wavefunction computation approaches to obtain MEP distributions. MEPSIM has a menu type interface to simplify the following tasks: creation of input files from output files of external programs (GAUSSIAN and AMPAC/MOPAC), setting the parameters for the current computation, and submitting jobs to the batch queues of the computer. MEPSIM has been coded in FORTRAN and its current version runs on VMS/VAX computers.     

Gradients of the Exchange-repulsion Energy in the General Effective Fragment Potential Method

Formulae for calculating the analytic gradients of the exchange-repulsion energy in the general effective fragment potential (EFP2) method are derived and implemented using a direct differentiation approach. The timings for the exchange repulsion gradient evaluations are approximately three times longer than the energy evaluations, orders of magnitude faster than a previous implementation. Since the direct differentiation approach is not approximate, the gradients can be used with confidence in molecular dynamics and Monte Carlo simulations with the EFP2 method.     

An Effective Zeta Potential Fitting Model for Sphere-Plate Interaction Force in Nanoparticle Suspensions

The silica sphere-plate interaction forces in zirconia nanoparticle suspensions have been successfully measured to explain how negligibly charged silica microspheres can be stabilized through the addition of highly charged zirconia nanoparticles. However, the influence of nanoparticle volume fraction on the stabilization as well as how various forces (the attractive van der Waals force, repulsive electrostatic force, and depletion force) contribute to the total interaction force still remains unclear. Therefore, an effective zeta potential fitting model is developed to explain the experimental interaction force curves based on a variable effective Debye length and a measured effective zeta potential using a continuum assumption.     

The electrostatic molecular potential of yeast tRNAPhe. III. The molecular potential and the steric acessibility associated with the phosphate groups

The molecular electrostatic potential of yeast tRNA^Phe is calculated at sites bridging the anionic oxygens of each of the 76 phosphate groups of the molecule. A quantitative measure of the steric accessibility of the anionic oxygens of the phosphates toward a spherical cation is presented. Both the resulting potentials and accessibilities are discussed in terms of the molecular and electronic structure of tRNA.     

Effective potential approach to bulk thermodynamic properties and surface tension of molecular fluids I. Single component n-alkane systems

The aim of this work is to develop spherically symmetric effective potentials allowing bulk thermodynamic properties and surface tension of molecular fluids to be predicted semiempirically by the use of statistical mechanical methods. Application is made to the straight chain alkane fluids from methane to decane. An effective Lennard-Jones potential is generated with temperature-dependent parameters fitted to the critical temperature and pressure and to Pitzer's acentric factor. Insertion of this potential into the generalised van der Waals (GvdW) density functional theory yields bulk properties in good agreement with experiments. The surface tension is overestimated for the longer alkane chains. In order to account for the surface tension, an independently adjustable attractive range of interaction is required and obtained through the use of square-well potentials chosen so as to leave the bulk thermodynamics unaltered while the attractive range is fitted to the surface tension at a single temperature. The GvdW theory, which includes binding energy, entropic and profile shape contributions, then generates surface tension estimates that are of good accuracy over the full range of available experimental data. It appears that, given a sufficiently flexible form, effective potentials combined with simple statistical mechanical theory can reproduce both bulk and non-uniform fluid data of great variety in an insighful and practically useful way.     

Production and properties of polyacenaphthylene. IV: Infuence of molecular structures and end groups on the elution volumes in gel permeation chromatography

Summary Low molecular weight polyacenaphthylenes with different end groups were synthesized by cationic and free-radical initiation. The polymers were fractionated by means of GPC. Polar as well as non-polar stationary phases proved suitable for the fractionation of polyacenaphthylene. The relationship, logM=f(V_e) is within the molecular weight range (M<10⁴) non-linear and depends on the initiator used or on the type of polyreaction that occured during the polymerisation. The elution volumes of polymers prepared by thermal initiation were comparably lower than those of polymers prepared by free-radical or cationic means.This difference is not due to end group effects but can be attributed to the structure of the polymer main chain.Third communication: Thomas Stelter, Jürgen Springer, Photoabbau von Polyacenaphthylen, Makromol. Chem.185, 1719 (1984)     

The atom assignment problem in automated de novo drug design. 2. A method for molecular graph and fragment perception

Summary If atom assignment onto 3D molecular graphs is to be optimized, an efficient scheme for placement must be developed. The strategy adopted in this paper is to analyze the molecular graphs in terms of cyclical and non-cyclical nodes; the latter are further divided into terminal and non-terminal nodes. Molecular fragments, from a fragments database, are described in a similar way. A canonical numbering scheme for the fragments and the local subgraph of the molecular graph enables fragments to be placed efficiently onto the molecular graph. Further optimization is achieved by placing similar fragments into bins using a hashing scheme based on the canonical numbering. The graph perception algorithm is illustrated in detail.     

Multi-way PLS modeling of structure–activity data by incorporating electrostatic and lipophilic potentials on molecular surface

We devised and elaborated a surface-based three-dimensional-quantitative structure–activity relationship (3D-QSAR) method, which had been proposed in the previous study. This approach can be applied to more general case where both the electrostatic and lipophilic potentials on molecular surface simultaneously change. The 3D coordinates of all sampling points on molecular surface are projected into a 2D map by Kohonen neural network (KNN). Each node in the map is coded by the associated molecular electrostatic potential (MEP) or molecular lipophilic potential (MLP) values. The electrostatic and lipophilic KNN maps are generated for each compound and the four-way array is constructed by collecting two KNN maps of all samples. The correlation between four-way array and biological activity is examined by four-way partial least-squares (PLS). For validation, the structure–activity data of estrogen receptor antagonists was investigated. The four-way PLS model gave the high statistics at calibration and validation stages. The coefficients of the four-way PLS model back-projected on molecular surface had a reasonable 3D distribution and it was nicely consistent with active site of the estrogen receptor which was recently made clear by X-ray crystallography.     

Tailoring approach for exploring electron densities and electrostatic potentials of molecular crystals

Experimental and theoretical studies of electron densities and the corresponding derived entities such as electrostatic potentials have been the primary means of understanding the chemical nature and electronic properties of crystalline substances. Conventional crystal calculation methods such as the embedded cluster models are capable of performing calculations on small and medium-sized molecules, while periodic ab initio methods can treat crystals with up to 200 atoms per unit cell. A linear scaling method, viz. the molecular tailoring approach, has recently been developed for obtaining ab initio quality one-electron properties. In the present study, the molecular tailoring approach is employed to generate electron density, electrostatic potential and interaction density maps with the ibuprofen crystal as a test case. The interaction density and electrostatic potential maps produced in the present work succinctly bring out the actual crystalline environment around a given reference molecule by including the interactions with atoms in its neighborhood. The results obtained from the molecular tailoring approach may thus be expected to enhance our understanding of the environment in the crystalline material with reasonably small computational effort.Contribution to the Jacopo Tomasi Honorary Issue     

The atom assignment problem in automated de novo drug design. 5. Tests for envelope-directed fragment placement based on molecular similarity

Summary The fragment placement method has been successfully extended to the problem of envelope-directed design. The atom assignment paradigm was based on molecular similarity between two molecular structures. A composite supersurface is defined to form the surface onto which the molecular fields are projected. The assignment process is then determined by using molecular similarity in the objective function to be optimized. In principle, this procedure is closely similar to that outlined in the previous paper for site-directed design. The rationale has been extensively tested on two benzodiazepine antagonists believed to bind to the same site.     

The atom assignment problem in automated de novo drug design. 4. Tests for site-directed fragment placement based on molecular complementarity

Summary Three previous papers in this series have outlined an optimization method for atom assignment in drug design using fragment placement. In this paper the procedure is rigorously tested on a selection of five ligand-protein co-crystals. The algorithm is presented with the molecular graph of the ligand, and the electrostatic/hydrophobic potential of the site, with the aim of creating a placement on the molecular graph which is as electrostatically complementary or hydrophobically similar to the site as possible. Various designer options were tested, including, where appropriate, hydrogen bonding and a restricted number of halogens. In most cases, the placement obtained was at least as good as the native ligand, if not significantly better.     

The concept of molecular machinery is useful for design of stimuli-responsive gene delivery systems in the mammalian cell

Since the first generation of molecular machines including photoresponsive crown ethers and its analogues was reported by Shinkai et al., a huge number of molecular machines exhibiting dynamic chemical and physical functions have been designed and developed. On the other hand, non-viral vectors are desired to possess conflicting properties to associate with DNA until reaching the nucleus as their final destination and dissociate from DNA there. In other words, non-viral vectors should work as a sort of molecular machinery. To overcome this dilemma, recently, much attention is focused on the development of the intelligent vectors, also called as ‘stimuli responsive vectors’ working as molecular machines. In this review, stimulus responsive gene delivery systems in which some structural factors and/or physiological properties are regulated in response to extracellular signals such as redox, pH, ultrasound, light, temperature, etc. are introduced as a new generation of non-viral vectors. These extracellular signals such as ultrasound, light, and temperature can be potent stimuli capable of site-, timing-, and duration-specific gene expression. This is a paper selected for “HGCS Japan Award of Excellence 2006”.     

Similarity searching in files of three-dimensional chemical structures: Representation and searching of molecular electrostatic potentials using field-graphs

This paper reports a method for the identification of those molecules in a database of rigid 3D structures with molecular electrostatic potential (MEP) grids that are most similar to that of a user-defined target molecule. The most important features of an MEP grid are encoded in field-graphs, and a target molecule is matched against a database molecule by a comparison of the corresponding field-graphs. The matching is effected using a maximal common subgraph isomorphism algorithm, which provides an alignment of the target molecule's field- graph with those of each of the database molecules in turn. These alignments are used in the second stage of the search algorithm to calculate the intermolecular MEP similarities. Several different ways of generating field-graphs are evaluated, in terms of the effectiveness of the resulting similarity measures and of the associated computational costs. The most appropriate procedure has been implemented in an operational system that searches a corporate database, containing ca. 173,000 3D structures.