Common failures in predicting crystal structures of ligand-protein complexes are investigated for three ligand-protein systems by a combined thermodynamic and kinetic analysis of the binding energy landscapes. Misdocked predictions in ligand-protein docking are classified as `soft' and `hard' failures. While a soft failure arises when the search algorithm is unable to find the global energy minimum corresponding to the crystal structure, a hard failure results from a flaw of the energy function to qualify the crystal structure as the predicted lowest energy conformation in docking simulations. We find that neither the determination of a single structure with the lowest energy nor finding the most common binding mode is sufficient to predict crystal structures of the complexes, which belong to the category of hard failures. In a proposed hierarchical approach, structural similarity clustering of the conformations, generated from equilibrium simulations with the simplified energy function, is followed by energy refinement with the AMBER force field. This protocol, that involves a hierarchy of energy functions, resolves some common failures in ligand-protein docking and detects crystallographic binding modes that were not found during docking simulations. 相似文献
Cyclodextrins (CDs) are useful functional excipients, which are being used to camouflage undesirable pharmaceutical characteristics, especially poor aqueous solubility, through the inclusion complexation process with insoluble drugs. The selection of more efficient cyclodextrin is important to improve the bioavailability of drugs. In this study, the complexing and solubilizing abilities toward poorly water-soluble monocyclic molecules of natural CDs (α-CD, β-CD, and γ-CD) were investigated using Monte Carlo (MC) docking simulations studies. These theoretical results closely agree with the experimental observation of the complex stability in water of the various guests–CD complexes. Host preferences, based on the experimentally determined stability constants between host CDs and guest molecules, show excellent correlation with the calculated interaction energies of corresponding complexes. The inclusion complex with the lower MC docking interaction energy shows a higher value of stability constant than that of the other complex, and the prediction accuracy of the preferred complex for 21 host–guest pairs is 100%. This result indicates that the MC docking interaction energy could be employed as a useful parameter to select more efficient cyclodextrin as a host for the bioavailability of insoluble drugs. In this study, β-CD shows greater solubilizing efficacies toward guest molecules than those of α-CD and γ-CD, with the exception of one case due to the structure of a guest molecule containing one lipophilic cyclic moiety. The surface area change of CDs and hydrogen bonding between the host and guest also work as major factors for the formation of the stable complex. 相似文献
We present a computer study of the association behavior of copolymer chains with a gradient part and soluble tail of variable length. As a simulation method we use dynamic Monte Carlo simulation on a simple cubic lattice with pair interaction parameters. The solvent quality and selectivity is modeled by the variation of pair interaction parameters between nearest neighbors on the lattice. The role of the length of soluble part in the self‐assembly and its effect on the structure of aggregates was the main goal of this work. The size and structure of aggregates were analyzed using an improved topological classification method which has been developed and tested in the present study. The structure and association numbers of aggregates were compared with those of linear diblock copolymers.
In this work, we report on a theoretical study of the contrast formation at Si/SixGe1–x interfaces in backscattered electron images of a scanning electron microscope. The contrast at the heterointerface is calculated for different atomic concentrations (0 < × < 1) and energies (E0 = 10 and 20 keV). The electron scattering phenomenon is simulated by employing a Monte Carlo method by using a single scattering approach. The signal intensity close to the interface shows a peak on the alloy side and a dip on the Si side. We explain this phenomenon by using the diffusion theory of the backscattered electrons. The spatial resolution increases by decreasing the Si concentration in the alloy side and by decreasing the beam energy. 相似文献
Fast determination of neighboring atoms is an essential step in molecular dynamics simulations or Monte Carlo computations, and there exists a variety of algorithms to efficiently compute neighbor lists. However, most of these algorithms are general, and not specifically designed for a given type of application. As a result, although their average performance is satisfactory, they might be inappropriate in some specific application domains. In this article, we study the case of detecting neighbors between large rigid molecules, which has applications in, e.g., rigid body molecular docking, Monte Carlo simulations of molecular self-assembly or diffusion, and rigid body molecular dynamics simulations. More precisely, we compare the traditional grid-based algorithm to a series of hierarchy-based algorithms that use bounding volumes to rapidly eliminate large groups of irrelevant pairs of atoms during the neighbor search. We compare the performance of these algorithms based on several parameters: the size of the molecules, the average distance between them, the cutoff distance, as well as the type of bounding volume used in the culling hierarchy (AABB, OBB, wrapped, or layered spheres). We demonstrate that for relatively large systems (> 100,000 atoms) the algorithm based on the hierarchy of wrapped spheres shows the best results and the traditional grid-based algorithm gives the worst timings. For small systems, however, the grid-based algorithm and the one based on the wrapped sphere hierarchy are beneficial. 相似文献
Molecular mechanics models have been applied extensively to study the dynamics of proteins and nucleic acids. Here we report the development of a third-generation point-charge all-atom force field for proteins. Following the earlier approach of Cornell et al., the charge set was obtained by fitting to the electrostatic potentials of dipeptides calculated using B3LYP/cc-pVTZ//HF/6-31G** quantum mechanical methods. The main-chain torsion parameters were obtained by fitting to the energy profiles of Ace-Ala-Nme and Ace-Gly-Nme di-peptides calculated using MP2/cc-pVTZ//HF/6-31G** quantum mechanical methods. All other parameters were taken from the existing AMBER data base. The major departure from previous force fields is that all quantum mechanical calculations were done in the condensed phase with continuum solvent models and an effective dielectric constant of epsilon = 4. We anticipate that this force field parameter set will address certain critical short comings of previous force fields in condensed-phase simulations of proteins. Initial tests on peptides demonstrated a high-degree of similarity between the calculated and the statistically measured Ramanchandran maps for both Ace-Gly-Nme and Ace-Ala-Nme di-peptides. Some highlights of our results include (1) well-preserved balance between the extended and helical region distributions, and (2) favorable type-II poly-proline helical region in agreement with recent experiments. Backward compatibility between the new and Cornell et al. charge sets, as judged by overall agreement between dipole moments, allows a smooth transition to the new force field in the area of ligand-binding calculations. Test simulations on a large set of proteins are also discussed. 相似文献
The recently introduced force field (FF) QMPFF3 is thoroughly validated in gas, liquid, and solid phases. For the first time, it is demonstrated that a physically well-grounded general purpose FF fitted exclusively to a comprehensive set of high level vacuum quantum mechanical data applied as it is to simulation of condensed phase provides high transferability for a wide range of chemical compounds. QMPFF3 demonstrates accuracy comparable with that of the FFs explicitly fitted to condensed phase data, but due to high transferability it is expected to be successful in simulating large molecular complexes. 相似文献
Dynamics of multilayer adsorption of macromolecules with different degree of polymerization is studied by coarse‐grained Monte Carlo simulations, focusing on both the interface macromolecule‐surface and chain–chain interaction in and out of equilibrium conditions. The interfacial interaction between the solid flat surface and the macromolecules is modeled by means of a Lennard–Jones potential, and inter‐ and intrachain interactions are simulated using bond angle, bond length, and Lennard–Jones potentials. The results show that local and conformational motions near the glass transition temperature promote configurations with minimal energy, which induce better space efficiency and favor aligned conformations at the interface. In this context, it is also found that restriction of movement, together with the connectivity effect exerted by the partially adsorbed segments, leads to a range of chain lengths that maximizes the molecular groups adsorbed. 相似文献
The association of Mg2+ and H2PO4? in water can give insights into Mg:phosphate interactions in general, which are very widespread, but for which experimental data is surprisingly sparse. It is studied through molecular dynamics simulations (>100 ns) by using the polarizable AMOEBA force field, and the association free energy is computed for the first time. Explicit consideration of outer‐sphere and two types of inner‐sphere association provides considerable insight into the dynamics and thermodynamics of ion pairing. After careful assessment of the computational approximations, the agreement with experimental values indicates that the methodology can be extended to other inorganic and biological Mg:phosphate interactions in solution. 相似文献
Many of the existing molecular simulation tools require the efficient identification of the set of nonbonded interacting atoms. This is necessary, for instance, to compute the energy values or the steric contacts between atoms. Cell linked-lists can be used to determine the pairs of atoms closer than a given cutoff distance in asymptotically optimal time. Despite this long-term optimality, many spurious distances are anyway computed with this method. Therefore, several improvements have been proposed, most of them aiming to refine the volume of influence for each atom. Here, we suggest a different improvement strategy based on avoiding to fill cells with those atoms that are always at a constant distance of a given atom. This technique is particularly effective when large groups of the particles in the simulation behave as rigid bodies as it is the case in simplified models considering only few of the degrees of freedom of the molecule. In these cases, the proposed technique can reduce the number of distance computations by more than one order of magnitude, as compared with the standard cell linked-list technique. The benefits of this technique are obtained without incurring in additional computation costs, because it carries out the same operations as the standard cell linked-list algorithm, although in a different order. Since the focus of the technique is the order of the operations, it might be combined with existing improvements based on bounding the volume of influence for each atom. 相似文献
The behavior of polyelectrolyte micelles with kinetically frozen hydrophobic cores in aqueous solutions was studied by Monte Carlo (MC) simulations and self-consistent field (SCF) calculations. Some results have already been published. The structure of water-soluble shells formed by weak polyelectrolytes, both pure and containing a low fraction of strongly hydrophobic units arranged either in a short sequence or distributed uniformly in the shell-forming chains was studied in detail. In the case of sequenced system, the analysis of concentration profiles of individual species reveals strong segregation and important self-organization of hydrophobic units in the shell. A comparison and critical analysis of results of MC and SCF methods is presented. 相似文献
