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1.
Athanassios Stavrakoudis 《Journal of molecular modeling》2009,15(2):165-171
In a recent study C8γ (complement protein) with Cys40Ala substitution and a C8α derived peptide with Cys164Ala substitution
were co-crystallized and their binding mode was revealed. Computer modeling and molecular dynamics simulations were performed
in order to check the hypothesis that the residues Ala164 of C8α and Ala40 of C8γ occupied the right position if cysteine
residues were in their place for disulfide bonding. Substitution of these two alanine residues with cysteine along with disulfide
bond creation via molecular modeling and subsequent molecular dynamics simulation of the complex corroborated the hypothesis,
which was also confirmed from recent crystallographic data. Average RMSD between backbone atoms of the indel peptide during
the MD trajectory in comparison with the corresponding sequence of crystal structure of the C8α/γ complex was found only 0.085
nm.
Figure Modeling the C*y/α comlexation. Ribbon representation of the C8y complexed with C8α indel peptide initial (green/cyan) X-ray
structure and the final MD conformation (magenta/orange) after imposing the disulfide link. Average RMSD between backbone
atoms of the indel peptide during MD trajectory in comparison with the corresponding sequence of crystal structure of the
C8α/y complex was found only 0.085nm.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
2.
Fernando Berton Zanchi Rafael Andrade Caceres Rodrigo Guerino Stabeli Walter Filgueira de Azevedo Jr. 《Journal of molecular modeling》2010,16(3):543-550
Purine nucleoside phosphorylase (PNP) (EC.2.4.2.1) is an enzyme that catalyzes the cleavage of N-ribosidic bonds of the purine
ribonucleosides and 2-deoxyribonucleosides in the presence of inorganic orthophosphate as a second substrate. This enzyme
is involved in purine-salvage pathway and has been proposed as a promising target for design and development of antimalarial
and antibacterial drugs. Recent elucidation of the three-dimensional structure of PNP by X-ray protein crystallography left
open the possibility of structure-based virtual screening initiatives in combination with molecular dynamics simulations focused
on identification of potential new antimalarial drugs. Most of the previously published molecular dynamics simulations of
PNP were carried out on human PNP, a trimeric PNP. The present article describes for the first time molecular dynamics simulations
of hexameric PNP from Plasmodium falciparum (PfPNP). Two systems were simulated in the present work, PfPNP in ligand free form, and in complex with immucillin and sulfate.
Based on the dynamical behavior of both systems the main results related to structural stability and protein-drug interactions
are discussed.
相似文献
3.
Realistic molecular models of one and two-centre catalytic active sites originating from the cleavage of a precursor material
known to give rise to an active double metal cyanide catalyst are described. Via periodic density functional calculations
the structure of the proposed catalytic sites are shown to be dependent on electrostatic and structural relaxation processes
occurring at the surfaces of the precursor material. It is shown how these effects may be adequately captured by small molecular
models of the active sites. The general methodology proposed should provide a computationally efficient basis for detailed
future studies into catalytic reactions over double metal cyanide materials.
Figure Reconstructed DMC [100]-surface: electrostatic potential mapped on charge density isosurface
This work has been originally presented on the Modelling and Design of Molecular Materials conference in Wrocław, Poland. 相似文献
4.
Rotational strengths in the far-UV of TEM-1 β-lactamase have been investigated with two theoretical models based on the matrix
method. The first model excludes, and a second includes, effects of the local electrostatic interactions on the chromophore
energies. Special attention is given to the contributions of the aromatic side-chain chromophores, and the mechanisms of generation
of rotational strengths are analyzed. The sensitivity of the computational models with respect to the structural changes of
the protein are discussed.
Figure Structure of TEM-1 β-lactamase. Both domains—α and αβ, the secondary structural elements and the aromatic and disulfide chromophores
are shown 相似文献
5.
Life has adapted to most environments on earth, including low and high temperature niches. The increased catalytic efficiency
and thermoliability observed for enzymes from organisms living in constantly cold regions when compared to their mesophilic
and thermophilic cousins are poorly understood at the molecular level. Uracil DNA glycosylase (UNG) from cod (cUNG) catalyzes
removal of uracil from DNA with an increased kcat and reduced Km relative to its warm-active human (hUNG) counterpart. Specific issues related to DNA repair and substrate binding/recognition
(Km) are here investigated by continuum electrostatics calculations, MD simulations and free energy calculations. Continuum electrostatic
calculations reveal that cUNG has surface potentials that are more complementary to the DNA potential at and around the catalytic
site when compared to hUNG, indicating improved substrate binding. Comparative MD simulations combined with free energy calculations
using the molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) method show that large opposing energies are involved
when forming the enzyme-substrate complexes. Furthermore, the binding free energies obtained reveal that the Michaelis-Menten
complex is more stable for cUNG, primarily due to enhanced electrostatic properties, suggesting that energetic fine-tuning
of electrostatics can be utilized for enzymatic temperature adaptation. Energy decomposition pinpoints the residual determinants
responsible for this adaptation.
Figure Electrostatic isosurfaces of cod uracil DNA glycosylase in complex with double stranded DNA 相似文献
6.
The three-dimensional (3D) structure of the catalytic domain of Gas1p, a protein belonging to the only family of β-(1,3)-glucan
transferases so far identified in yeasts and some pathogenic fungi (family GH-72), has been predicted by combining results
derived from threading methods, multiple sequence alignments and secondary-structure predictions. The 3D model has allowed
the identification of several residues that are predicted to play a crucial role in structural integrity, substrate recognition
and catalysis. In particular, the model of the catalytic domain can be useful for designing site-directed mutagenesis experiments
and for developing inhibitors of Gas1p enzymatic activity.
Figure Three-dimensional models of the Gas1p catalytic domain as predicted using as template 7A3H (PDB code) protein
Electronic Supplementary Material Supplementary material is available for this article at 相似文献
7.
The high incidence of thrombembolic diseases justifies the development of new antithrombotics. The search for a direct inhibitor has resulted in the synthesis of a considerable number of low molecular weight molecules that inhibit human α-thrombin potently. However, efforts to develop an orally active drug remain in progress as the most active inhibitors with a highly basic P1 moiety exhibit an unsatisfactory bioavailability profile. In our previous work we solved several X-ray structures of human α-thrombin in complexes with (1) novel bicyclic arginine mimetics attached to the glycylproline amide and pyridinone acetamide scaffold and (2) inhibitors with a novel aza scaffold and with charged or neutral P1 moieties. In the present contribution, we correlate the structures of the complex between these inhibitors and the protein with the calculated free energy of binding. The energy of solvation was calculated using the Poisson–Boltzmann approach. In particular, the requirements for successful recognition of an inhibitor at the protein’s active site pocket S1 are discussed.
Figure We report here on free energy of binding analysis of thrombin inhibitors with novel aza scaffold and novel bicyclic arginine mimetics in S1 pocket of thrombin 相似文献
8.
Frans T. I. Marx Johan H. L. Jordaan Hermanus C. M. Vosloo 《Journal of molecular modeling》2009,15(11):1371-1381
The productive self-metathesis reaction of 1-octene in the presence of the Phobcat precatalyst [RuCl2(Phoban-Cy)2(=CHPh)] using density functional theory was investigated and compared to the Grubbs 1 precatalyst [RuCl2(PCy3)2(=CHPh)]. At the GGA-PW91/DNP level, the geometry optimization of all the participating species and the PES scans of the various
activation and catalytic cycles in the dissociative mechanism were performed. The formation of the catalytically active heptylidene
species is kinetically and thermodynamically favored, while the formation of trans-tetradecene is thermodynamically favored.
相似文献
9.
Gargallo R Cedano J Mozo-Villarias A Querol E Oliva B 《Journal of molecular modeling》2006,12(6):835-845
The dependence of some molecular motions in the enzyme 1,3-1,4-β-glucanase from Bacillus licheniformis on temperature changes and the role of the calcium ion in them were explored. For this purpose, two molecular dynamics simulated trajectories along 4 ns at low (300 K) and high (325 K) temperatures were generated by the GROMOS96 package. Several structural and thermodynamic parameters were calculated, including entropy values, solvation energies, and essential dynamics (ED). In addition, thermoinactivation experiments to study the influence of the calcium ion and some residues on the activity were conducted. The results showed the release of the calcium ion, which, in turn, significantly affected the movements of loops 1, 2, and 3, as shown by essential dynamics. These movements differ at low and high temperatures and affect dramatically the activity of the enzyme, as observed by thermoinactivation studies.
The first two authors contributed equally to this work 相似文献
10.
Nitrile hydratase (NHase) is an enzyme containing non-corrin Co3+ in the non-standard active site. NHases from Pseudonocardia thermophila JCM 3095 catalyse hydration of nitriles to corresponding amides. The efficiency of the enzyme is 100 times higher for aliphatic
nitriles then aromatic ones. In order to understand better this selectivity dockings of a series of aliphatic and aromatic
nitriles and related amides into a model protein based on an X-ray structure were performed. Substantial differences in binding
modes were observed, showing better conformational freedom of aliphatic compounds. Distinct interactions with postranslationally
modified cysteines present in the active site of the enzyme were observed. Modeling shows that water molecule activated by
a metal ion may easily directly attack the docked acrylonitrile to transform this molecule into acryloamide. Thus docking
studies provide support for one of the reaction mechanisms discussed in the literature.
Figure Crystalographic structure of Pseudonocardia thermophila JCM 3095 nitrile hydratase (a) and the non-standard active site (b) 相似文献
11.
Aminophosphine oxides and aminophosphonates are, in general, very stable compounds. However, following phosphorus–carbon bond
cleavage in aqueous acidic media these compounds sometimes decompose to phosphonic acids derivatives (PIII). Despite some controversy in the literature, careful analysis supported by theoretical studies leads to the conclusion that
decomposition to PIII derivatives proceeds via an elimination reaction.
Figure The decomposition of α-aminophosphine oxides to phosphonic acid derivatives (PIII) 相似文献
12.
Quan Luo Yuan Yao Wei-Wei Han Yi-Han Zhou Ze-Sheng Li 《Journal of molecular modeling》2009,15(9):1125-1132
The 3D structure of a novel epoxide hydrolase from Aspergillus niger SQ-6 (sqEH) was constructed by using homology modeling
and molecular dynamics simulations. Based on the 3D model, Asp191, His369 and Glu343 were predicted as catalytic triad. The
putative active pocket is a hydrophobic environment and is rich in some important non—polar residues (Pro318, Trp282, Pro319,
Pro317 and Phe242). Using three sets of epoxide inhibitors for docking study, the interaction energies of sqEH with each inhibitor
are consistent with their inhibitory effects in previous experiments. Moreover, a critical water molecule which closes to
the His369 was identified to be an ideal position for the hydrolysis step of the reaction. Two tyrosine residues (Tyr249 and
Tyr312) are able to form hydrogen bonds with the epoxide oxygen atom to maintain the initial binding and positioning of the
substrate in the active pocket. These docked complex models can well interpret the substrate specificity of sqEH, which could
be relevant for the structural—based design of specific epoxide inhibitors.
Figure 相似文献
13.
Semi-empirical quantum mechanics calculations using AM1 (Austin Method 1) were carried out for various host-guest combinations of α-cyclodextrin and mono-halogen benzoic acids. The energetically favorable inclusion structures were identified. The AM1 results show that α-cyclodextrin complexes with mono-halogen benzoic acid acids (where the halogen is chlorine, bromide, iodine) as guest compounds are more stable in the “head first” position than in the “tail-first” position for meta and para isomers while ortho mono-halogen benzoic acids complexes with α-cyclodextrin are more stable in “tail-first” position. The calculated structures were found to be in good agreement with those obtained from crystalographic databases.
相似文献
14.
Aimed at achieving a good understanding of the 3-dimensional structures of human α1A-adrenoceptor (α1A-AR), we have successfully developed its homology model based on the crystal structure of β2-AR. Subsequent structural refinements were performed to mimic the receptor’s natural membrane environment by using molecular
mechanics (MM) and molecular dynamics (MD) simulations in the GBSW implicit membrane model. Through molecular docking and
further simulations, possible binding modes of subtype-selective α1A-AR antagonists, Silodosin, RWJ-69736 and (+)SNAP-7915, were examined. Results of the modeling and docking studies are qualitatively
consistent with available experimental data from mutagenesis studies. The homology model built should be very useful for designing
more potent subtype-selective α1A-AR antagonists and for guiding further mutagenesis studies.
Figure The superposition of β2-AR crystal structure (gold ribbons) and α1A-AR homology model (blue ribbons) 相似文献
15.
3D-QSAR and molecular docking analysis were performed to explore the interaction of estrogen receptors (ERα and ERβ) with
a series of 3-arylquinazolinethione derivatives. Using the conformations of these compounds revealed by molecular docking,
CoMFA analysis resulted in the first quantitative structure-activity relationship (QSAR) and first quantitative structure-selectivity
relationship (QSSR) models predicting the inhibitory activity against ERβ and the selectivity against ERá. The q2 and R2 values, along with further testing, indicate that the obtained 3D-QSAR and 3D-QSSR models will be valuable in predicting
both the inhibitory activity and selectivity of 3-arylquinazolinethione derivatives for these protein targets. A set of 3D
contour plots drawn based on the 3D-QSAR and 3D-QSSR models reveal modifications of substituents at C2 and C5 of the quinazoline
which my be useful to improve both the activity and selectivity of ERβ/ ERα. Results showed that both the steric and electrostatic
factors should appropriately be taken into account in future rational design and development of more active and more selective
ERβ inhibitors for the therapeutic treatment of osteoporosis.
Figure Structures of ERβ binding with compounds 1aar, 1ax and 1aag obtained from molecular docking 相似文献
16.
Richard A. J. O’Hair Craig M. Williams Timothy Clark 《Journal of molecular modeling》2010,16(3):559-565
We have used density-functional theory to investigate the neighboring-group stabilization of iodine, arsenic, and phosphorus-centered
oxyanion moieties in species such as deprotonated 2-iodoxybenzoic acid (IBX) and its analogs. The magnitudes of different
stabilizing effects and further candidates for analogous stabilization are analyzed.
相似文献
17.
This article describes in a sequential fashion how ab initio quantum mechanical methods can be applied to study the pharmacophoric
features of drugs. It also describes how accurate drug–receptor interaction calculations can guide the careful design of balanced
dual inhibitors, which form an important class of second generation drugs. As an example, the authors have chosen balanced
inhibitors of angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) as modern antihypertensive drugs. A unified, accurate,
in silico design approach is presented, encompassing all steps from pharmacophore derivation to complete understanding of
mechanistic aspects leading to drug design.
相似文献
18.
Microsomal cytochrome P450 family 1 enzymes has great importance in the bioactivation of mutagens. P450 catalyzed reactions
involve a wide range of substrates, and this versatality is reflected in a structural diversity, evident in the active sites
of available P450 structures. This structure offers a template to study further structure-function relationships of alternative
substrates and other cytochrome P450 family 1 members. In this paper, we document a homology model of CYP P450 1A1 from Homo
sapiens, developed on the basis of template crystal structure of human microsomal P450 1a2 in complex with inhibitor (PDB
Id: 2HI4). Homology modeling is performed at the programs, both in the commercial and public realms. We tried to explore CYP1A1
as a potential target for anticancer chemotherapy. To gain an insight into the binding of ligands with enzyme, protein-ligand
complex was developed by including information about the known ligand as spatial restraints and optimizing the mutual interactions
between the ligand and the binding site. Active site characterization and the study for involvement of specific aminoacids
in binding with ligand, facilitates structure based inhibitor design. This study should prove useful in the design and development
of potential novel anticancer agents.
Figure The refined structure of homology model of CYP1A1 相似文献
19.
Machado E Kaczmarski M Braida B Ordejón P Garg D Norman J Cheng H 《Journal of molecular modeling》2007,13(6-7):861-864
Processes for the deposition of copper films on transition metal barrier layers by means CVD using organometallic precursors
are often found to lead to poor adhesion characteristics of the grown film. By means of first-principles molecular dynamics
simulations, we show that the source of the problem is the strong reactivity of the surfaces toward the precursors, which
decompose spontaneously upon contact with the surface leading to contamination of the interface. Our simulations consider
Ti, Ta, and W as barrier layers, and Cu(hfac)-(tmvs) as precursor. In contrast, we show that surfaces of these metals properly
passivated with nitrogen, in such a way that only N atoms are exposed on the surface, are much less active and do not lead
to decomposition of the precursor. We propose this passivation procedure as a practical solution to the adhesion problem.
Figure CupraSelect on the WN (100) surface 相似文献
20.
Grzywa R Dyguda-Kazimierowicz E Sieńczyk M Feliks M Sokalski WA Oleksyszyn J 《Journal of molecular modeling》2007,13(6-7):677-683
Urokinase-type plasminogen activator (uPA) is a trypsin-like serine protease that plays a crucial role in angiogenesis process.
In addition to its physiological role in healthy organisms, angiogenesis is extremely important in cancer growth and metastasis,
resulting in numerous attempts to understand its control and to develop new approaches to anticancer therapy. The α-aminoalkylphosphonate
diphenyl esters are well known as highly efficient serine protease inhibitors. However, their mode of binding has not been
verified experimentally in details. For a group of average and potent phosphonic inhibitors of urokinase, flexible docking
calculations were performed to gain an insight into the active site interactions responsible for observed enzyme inhibition.
The docking results are consistent with the previously suggested mode of inhibitors binding. Subsequently, rigorous ab initio
study of binding energy was carried out, followed by its decomposition according to the variation–perturbation procedure to
reveal stabilization energy constituents with clear physical meaning. Availability of the experimental inhibitory activities
and comparison with theoretical binding energy allows for the validation of theoretical models of inhibition, as well as estimation
of the possible potential for binding affinity prediction. Since the docking results accompanied by molecular mechanics optimization
suggested that several crucial active site contacts were too short, the optimal distances corresponding to the minimum ab
initio interaction energy were also evaluated. Despite the deficiencies of force field-optimized enzyme-inhibitor structures,
satisfactory agreement with experimental inhibitory activity was obtained for the electrostatic interaction energy, suggesting
its possible application in the binding affinity prediction.
Figure The comparison of an arrangement of inhibitors within uPA active. Amino acid residues form S1 pocket that binds the variable
part of inhibitor molecules 相似文献