Analysis of biomolecular chaos in aqueous solution

 The tropoelastin peptide CH₃CO-Gly-Leu-Gly-Gly-NHCH₃ has been modeled in aqueous solution by means of force-field molecular dynamics simulations and its motion characterized using nonlinear dynamics theory. The trajectory R(t) of the representative system point in configurational space has been considered. Fractional Brownian motion with anomalous diffusion is observed resulting from chaotic dynamics of molecules on fractal media. The chaos of the peptide is a consequence of nonlinear effects such as hydrodynamic interactions of the chain due to the poor solvent role of water. The viscous drag is pointed out and should be due to the percolation network of hydrogen-bonded water molecules. The method of reconstruction of the phase space using the embedding theorem is applied to the trajectory D _ee(t) of the peptide end-to-end distance. The existence of a low-dimensional chaotic attractor for dissipative systems has been demonstrated. The dynamical high-entropy state of the peptide in solution strengthens the transition-to-chaos mechanism for the elastin elasticity. Received: 14 September 1999 / Accepted: 3 February 2000 / Published online: 2 May 2000     

An atomistic model of passive membrane permeability: application to a series of FDA approved drugs

We apply an atomistic model of passive membrane permeability to a series of weakly basic drugs. The computational model uses conformational sampling in combination with an all-atom force field and implicit solvent model to estimate relative passive membrane permeabilities. The model does not require the use of training data for rank-ordering compounds, and as such represents a different approach from the more commonly employed QSPR models. We compare the computational results to previously published experimental PAMPA and Caco-2 permeabilities.     

Recent advances in molecular dynamics simulation towards the realistic representation of biomolecules in solution

Coupled advances in empirical force fields and classical molecular dynamics simulation methodologies, combined with the availability of faster computers, has lead to significant progress towards accurately representing the structure and dynamics of biomolecular systems, such as proteins, nucleic acids, and lipids in their native environments. Thanks to these advances, simulation results are moving beyond merely evaluating force fields, displaying expected structural fluctuations, or demonstrating low root-mean-squared deviations from experimental structures and now provide believable structural insight into a variety of processes such as the stabilization of A-DNA in mixed water and ethanol solution or reversible β-peptide folding in methanol. The purpose of this overview is to take stock of these recent advances in biomolecular simulation and point out some common deficiencies exposed in longer simulations. The most significant methodological advances relate to the development of fast methods to properly treat long-range electrostatic interactions, and in this regard the fast Ewald methods are becoming the de facto standard. Received: 9 April 1998 / Accepted: 21 May 1998 / Published online: 13 August 1998     

An approximate but efficient method to calculate free energy trends by computer simulation: Application to dihydrofolate reductase-inhibitor complexes

Summary Derivatives of free energy differences have been calculated by molecular dynamics techniques. The systems under study were ternary complexes of Trimethoprim (TMP) with dihydrofolate reductases of E. coli and chicken liver, containing the cofactor NADPH. Derivatives are taken with respect to modification of TMP, with emphasis on altering the 3-, 4- and 5-substituents of the phenyl ring. A linear approximation allows the encompassing of a whole set of modifications in a single simulation, as opposed to a full perturbation calculation, which requires a separate simulation for each modification. In the case considered here, the proposed technique requires a factor of 1000 less computing effort than a full free energy perturbation calculation. For the linear approximation to yield a significant result, one has to find ways of choosing the perturbation evolution, such that the initial trend mirrors the full calculation. The generation of new atoms requires a careful treatment of the singular terms in the non-bonded interaction. The result can be represented by maps of the changed molecule, which indicate whether complex formation is favoured under movement of partial charges and change in atom polarizabilities. Comparison with experimental measurements of inhibition constants reveals fair agreement in the range of values covered. However, detailed comparison fails to show a significant correlation. Possible reasons for the most pronounced deviations are given.     

用分子动力学模拟方法研究磺酰脲化合物在溶液中构象的变化

农药化合物通常在溶液中起作用 ,由于溶剂的作用 ,其结构与在固体状态下有很大不同 ,因此研究农药化合物分子在溶液中结构的变化 ,对于了解农药作用机理以及与受体的相互作用是非常有意义的 .磺酰脲是一种超高效低毒 ,有着重要用途的除草剂 ,因而得到了广泛的应用与研究 .我们曾对其结构与性能的关系进行了系统的研究 ,并在此基础上建立了一个能解释若干实验规律的初级作用模型 [1] .但是以往有关结构的研究都是针对晶体和真空中的自由构象进行的 .由于在实际溶液中的结构情况会有所不同 ,因此 ,研究分子在不同溶液中的行为具有十分重要的意…     

The separation of enantiomers on modified cyclodextrin columns: Measurements and molecular modeling

The enantiomers of 2-chloropropionic acid methyl ester, cis-pinane, 2-bromoethylbenzene, 2-bromobutane, 2-hydroxybutane trifluoroacetyl ester, and styrene oxide have been resolved on an octakis-(3-O-butyryl-2,6-di-O-pentyl)-γ-cyclo-dextrin capillary column, and the separation of the styrene oxide enantiomers has also been studied on columns coated with octakis-(3-O-trifluoroacetyl-2,6-di-O-pentyl)-cyclodextrin, octakis-(2,3,6-tri-O-pentyl)-γ-cyclodextrin, heptakis-(3-O-trifluoroacetyl-2,6-di-O-pentyl)-β -cyclodextrin, and heptakis-(2,3,6-tri-O-methyl)-β-cyclodextrin. Thermodynamic parameters (ΔG, ΔH, and ΔS) were determined from variable temperature measurements. The inclusion complexes containing styrene oxide were also studied by molecular modeling techniques. It has been found that a combined molecular mechanics–molecular dynamics approach may be a valuable tool for rationalizing the qualitative trends observed in the experimental separation factors. For the inclusion complexes considered here it is shown that the orientation of the guest relative to the cyclodextrin host is determined by the size and polarity of the cyclodextrin.     

Force field evaluation for biomolecular simulation: free enthalpies of solvation of polar and apolar compounds in various solvents.

Recently, the GROMOS biomolecular force field parameter set 53A6--which has been parametrized to reproduce experimentally determined free enthalpies of hydration and solvation in cyclohexane of amino acid side-chain analogs--was presented. To investigate the transferability of the new parameter set, we calculated free enthalpies of solvation of a range of polar and apolar compounds in different solvents (methanol, dimethyl sulfoxide (DMSO), acetonitrile, and acetone) from molecular dynamics simulations using the GROMOS 53A6 force field. For methanol and DMSO, parameters were used that are available in the 53A6 parameter set. For acetonitrile, a recently developed model was taken and for acetone, two models available in literature were used. We found that trends in and values for the solvation free enthalpies are in satisfactory agreement with experiment, except for the solvation in acetone for which deviations from experiment can be explained in terms of the properties of the models used.     

Effective Born radii in the generalized Born approximation: the importance of being perfect

Generalized Born (GB) models provide, for many applications, an accurate and computationally facile estimate of the electrostatic contribution to aqueous solvation. The GB models involve two main types of approximations relative to the Poisson equation (PE) theory on which they are based. First, the self-energy contributions of individual atoms are estimated and expressed as "effective Born radii." Next, the atom-pair contributions are estimated by an analytical function f(GB) that depends upon the effective Born radii and interatomic distance of the atom pairs. Here, the relative impacts of these approximations are investigated by calculating "perfect" effective Born radii from PE theory, and enquiring as to how well the atom-pairwise energy terms from a GB model using these perfect radii in the standard f(GB) function duplicate the equivalent terms from PE theory. In tests on several biological macromolecules, the use of these perfect radii greatly increases the accuracy of the atom-pair terms; that is, the standard form of f(GB) performs quite well. The remaining small error has a systematic and a random component. The latter cannot be removed without significantly increasing the complexity of the GB model, but an alternative choice of f(GB) can reduce the systematic part. A molecular dynamics simulation using a perfect-radii GB model compares favorably with simulations using conventional GB, even though the radii remain fixed in the former. These results quantify, for the GB field, the importance of getting the effective Born radii right; indeed, with perfect radii, the GB model gives a very good approximation to the underlying PE theory for a variety of biomacromolecular types and conformations.     

Molecular dynamics simulation of acetamide solvation using interaction energy components: Application to structural and energy properties

Molecular dynamics simulation of an aqueous solution of acetamide was performed using Lennard–Jones 12-6-1 potentials to describe the solute–solvent interactions, and TIP3P to describe the water–water interactions. The Morokuma decomposition scheme and the ESIE solute atomic charges were used to reproduce the molecular parameters of the solute–water interaction potential. The results showed that the functions that use the EX-PL-DIS-ES interaction model lead to good values of the structural and energy properties (in particular, the hydration shell and the solvation energies) when they are compared with those from using AMBER-derived parameters, and with the available theoretical and experimental data.     

On the suitability of the virial equation for modeling the solubility of solids in supercritical fluids

Five model systems, the van der Waals fluid, the Soave-Redlich-Kwong fluid, the Peng-Robinson fluid, the hard-sphere fluid, and the square-well fluid, are used to examine the performance of the truncated virial expansion in describing the fugacity of a solute at infinite dilution in a solvent. It is demonstrated that the virial fugacity results deteriorate at significantly lower densities as the solute becomes larger. This has consequences for attempts to describe the solubility of solids in supercritical fluids, where the virial expansion, truncated after the third virial coefficient, has been considered as a modeling option. The results of this work suggest that, for the densities and solute-to-solvent size ratios commonly encountered in supercritical extraction, the truncated virial expansion should not be expected to describe correctly the solute fugacity, and therefore any success it has in fitting solubility data should be viewed with caution.     

Molecular mechanics and dynamics study of DNA-furocoumarins complexes: Effect of methylation of the angular derivatives on the intercalation geometry

Summary Results of molecular mechanics calculations on intercalation complexes between DNA and angelicin derivatives: angelicin, 4-methylangelicin, 5-methylangllicin, 4,4-dimethylangelicin, 4,5-dimethylangelicin, 4,6,4-trimethylangelicin and 4,6,5-trimethylangelicin, are presented. The correlation between the presence of methyl groups and an increase in DNA photobinding affinity is discussed on the basis of the molecular structures. The influence of the orientation of the angelicins within the intercalation cavity is also discussed. Finally, the consequences of the dynamical behaviour of angelicin in the intercalation cite are studied.Abbreviations CNDO complete neglect of differential overlap - NMR nuclear magnetic resonance - rms root mean square - UV-A ultraviolet light of class A (320<<400 nm)     

How proteins get in touch: interface prediction in the study of biomolecular complexes

Protein-protein interface prediction is a booming field, with a substantial growth in the number of new methods being published the last two years. The increasing number of available three-dimensional structures of protein-protein complexes has enabled large-scale statistical analyses of protein interfaces, considering evolutionary, physicochemical and structural properties. Successful combinations of these properties have led to more accurate interface predictors in recent years. In addition to parametric combination, machine learning algorithms have become popular. In the meantime, assessing the absolute and relative performance of interface predictors remains very difficult: This is due to differences in both the output of the various interface predictors, and in the evaluation criteria used by their respective authors. This review provides an overview of the state of the art in the field, and discusses the performance of existing interface predictors. The focus is mainly on protein-protein interface prediction, although most issues are also valid for other kinds of interface prediction.     

Solvent Effects on the UV (n → π*) and NMR (17O) Spectra of Acetone in Aqueous Solution: Development and Validation of a Modified AMBER Force Field for an Integrated MD/DFT/PCM Approach

A modified AMBER force field has been developed and used to compute UV and NMR spectra of acetone in aqueous solution by an integrated computational tool rooted in the density functional theory, the polarizable continuum model, and classical molecular dynamics. The results show that, provided that classical force fields are carefully reparameterized and validated, they can be part of a robust and effective approach, which can be used also by non-specialists and provides a general and powerful complement to experimental techniques.     

Molecular modeling of interfaces between cellulose crystals and surrounding molecules: Effects of caprolactone surface grafting

A technical problem in cellulosic nanocomposite materials is the weak interaction between hydrophilic cellulose and hydrophobic polymer matrices. One approach to solve this difficulty is to chemically graft monomers of the matrix polymer onto the cellulose surface. An important question is to understand the effect such surface modification has on the interfacial properties. Semi-empirical approaches to estimate work of adhesion based on surface energies do not provide information on specific molecular interactions. Details about these interactions were obtained using molecular dynamics (MD) simulation. Cellulose interfaces with water and caprolactone medium were modeled with different amounts of grafted caprolactone. The modification lead to an increased work of adhesion between the surface and its surrounding medium. Furthermore, the MD simulations showed that the interaction between cellulose, both modified and non-modified, and surrounding medium is dominated by Coulomb interactions, predominantly as hydrogen bonds.     

Molecular modeling of the neurophysin I/oxytocin complex

Neurophysins I and II (NPI and NPII) act in the neurosecretory granules as carrier proteinsfor the neurophyseal hormones oxytocin (OT) and vasopressin (VP), respectively. The NPI/OTfunctional unit, believed to be an (NPI/OT)2 heterotetramer, was modeled using low-resolution structure information, viz. the C carbon atom coordinates of the homologousNPII/dipeptide complex (file 1BN2 in the Brookhaven Protein Databank) as a template. Itsall-atom representation was obtained using standard modeling tools available within theINSIGHT/Biopolymer modules supplied by Biosym Technologies Inc. A conformation of theNPI-bound OT, similar to that recently proposed in a transfer NOE experiment, was dockedinto the ligand-binding site by a superposition of its Cys1-Tyr2 fragment onto the equivalentportion of the dipeptide in the template. The starting complex for the initial refinements wasprepared by two alternative strategies, termed Model I and Model II, each ending with a100 ps molecular dynamics (MD) simulation in water using the AMBER 4.1 force field. The freehomodimer NPI2 was obtained by removal of the two OT subunits from their sites, followedby a similar structure refinement. The use of Model I, consisting of a constrained simulatedannealing, resulted in a structure remarkably similar to both the NPII/dipeptide complex anda recently published solid-state structure of the NPII/OT complex. Thus, Model I isrecommended as the method of choice for the preparation of the starting all-atom data forMD. The MD simulations indicate that, both in the homodimer and in the heterotetramer, the310-helices demonstrate an increased mobility relative to the remaining body of the protein.Also, the C-terminal domains in the NPI2 homodimer are more mobile than the N-terminalones. Finally, a distinct intermonomer interaction is identified, concentrated around its mostprominent, although not unique, contribution provided by an H-bond from Ser25O in one NPI unit to Glu81 O in the other unit. This interaction is present in the heterotetramer(NPI/OT)2 and absent or weak in the NPI2 homodimer. We speculate that this interaction,along with the increased mobility of the 310-helices and the carboxy domains, may contributeto the allosteric communication between ligand binding and NPI dimerization.     

Molecular modeling of the olefin metathesis by tungsten(0) carbene complexes

Density functional and second-order Moller–Plesset theory were used to model W(0) carbene mediated homogeneous metathesis reaction of propylene. The calculations show that the rate determining step of the metathesis is the initiation. After the initiation has been completed the rate determining step becomes dissociation of olefin–metallocarbene complex. The low stereoselectivity of the olefin metathesis reaction is due to the close matching of activation energies for cis and trans isomer formation and the fast cis–trans isomerization caused by the catalysts. The non-productive olefin metathesis reaction always dominates the reaction mixture owing to its very low activation energy. The electronic structure of metal carbene olefin complexes can be described as a combination of donor–acceptor interactions between HOMO of the olefin and LUMO of metal carbene located at carbene carbon on the one hand, and the Dewar, Chatt and Duncanson back donation scheme on the other.     

Energy and capacity time correlation functions for investigation of vibrational energy relaxation

Vibrational energy relaxation of a diatomic solute in a liquid solvent is investigated by means of the generalized Langevin equation. The vibrational energy, velocity and capacity time correlation functions (TCFs) are considered. It is shown that the detailed structure of the energy TCF contains an initial fast (subpicosecond) decay segment that is followed by weak oscillations on the background of an exponential relaxation curve. The direct method for evaluating the relaxation rate constant from equilibrium molecular dynamics simulations of a flexible solute is proposed and implemented. The closed form expressions for the memory function and for the relaxation rate constant in terms of quantities accessible from the simulations are derived. The simulation results for rigid and flexible solutes are compared and analyzed.