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1.
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
2.
The reverse-docking of a TADDOL catalyst to rigid transition-state (TS) representations of an asymmetric hetero-Diels–Alder reaction is described. The resulting docking poses represent a simplified geometric model of the TS for the catalyzed reaction. The conformational space of the catalyst in proximity to the catalyst-free TS models is sampled stochastically and the energetically favored poses are subjected to a clustering procedure to highlight structural attributes compatible with organocatalysis. Each pose is scored and ranked based on its molecular-mechanics docking energy. The reverse-docking procedure reveals a clear energetic trend in favor of the experimentally preferred product enantiomers. Analysis of the best poses suggests a geometric model that is consistent with principles of molecular recognition, catalysis, and experimental data.
相似文献
3.
The conformational stability of the extended antiparallel dimer structure of Met-enkephalin in water was analyzed by examining the hydration structure of enkephalin using molecular dynamics simulations. The result shows that, despite of the hydrophicility of the terminal atoms in the pentapeptide, the main contributor for the stability of the dimer in water is the four intermolecular hydrogen bonds between the Gly2 and Phe4 groups. The three-dimensional model of the δ-opioid pharmacophore for this dimer structure was also established. Such a model was demonstrated to match the δ-opioid pharmacophore query derived from the non-peptides SIOM, TAN-67, and OMI perfectly. This result thus strongly supports the assumption that the dimer structure of Met-enkephalin is a possible δ-receptor binding conformation.
Figure Schematic model of the extended antiparallel dimer structure of Met-enkephalin 相似文献
4.
We performed three 3-ns molecular dynamics simulations of d(CGCGAATTCGCG)2 using the AMBER 8 package to determine the effect of salt concentration on DNA conformational transitions. All the simulations
were started with A-DNA, with different salt concentrations, and converged with B-DNA with similar conformational parameters.
However, the dynamic processes of the three MD simulations were very different. We found that the conformation transition
was slow in the solution with higher salt concentration. To determine the cause of this retardation, we performed three additional
1.5-ns simulations starting with B-DNA and with the salt concentrations corresponding to the simulations mentioned above.
However, astonishingly, there was no delayed conformation evolution found in any of the three simulations. Thus, our simulation
conclusion is that higher salt concentrations slows the A → B conformation transition, but have no effect on the final stable
structure.
Figure A-DNA and B-DNA. (a) is the canonical A-DNA, and (b) is the canonical B-DNA. Looking from the central major groove 相似文献
5.
6.
Spiwok V Lipovová P Skálová T Dusková J Dohnálek J Hasek J Russell NJ Králová B 《Journal of molecular modeling》2007,13(4):485-497
Enzymes from cold-adapted species are significantly more active at low temperatures, even those close to zero Celsius, but
the rationale of this adaptation is complex and relatively poorly understood. It is commonly stated that there is a relationship
between the flexibility of an enzyme and its catalytic activity at low temperature. This paper gives the results of a study
using molecular dynamics simulations performed for five pairs of enzymes, each pair comprising a cold-active enzyme plus its
mesophilic or thermophilic counterpart. The enzyme pairs included α-amylase, citrate synthase, malate dehydrogenase, alkaline
protease and xylanase. Numerous sites with elevated flexibility were observed in all enzymes; however, differences in flexibilities
were not striking. Nevertheless, amino acid residues common in both enzymes of a pair (not present in insertions of a structure
alignment) are generally more flexible in the cold-active enzymes. The further application of principle component analysis
to the protein dynamics revealed that there are differences in the rate and/or extent of opening and closing of the active
sites. The results indicate that protein dynamics play an important role in catalytic processes where structural rearrangements,
such as those required for active site access by substrate, are involved. They also support the notion that cold adaptation
may have evolved by selective changes in regions of enzyme structure rather than in global change to the whole protein.
Figure Collective motions in Cα atoms of the active site of cold-active xylanase
Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. 相似文献
7.
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
8.
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
9.
Oliver Mirus Tihana Bionda Arndt von Haeseler Enrico Schleiff 《Journal of molecular modeling》2009,15(8):971-982
Transport of polypeptides across membranes is a general and essential cellular process utilised by molecular machines. At
least one component of these complexes contains a domain composed of three tetratricopeptide repeat (3-TPR) motifs. We have
focussed on the receptor Toc64 to elucidate the evolved functional specifications of its 3-TPR domain. Toc64 is a component
of the Toc core complex and functionally replaces Tom70 at the outer membrane of mitochondria in plants. Its 3-TPR domain
recognises the conserved C-terminus of precursor-bound chaperones. We built homology models of the 3-TPR domain of chloroplastic
Toc64 from different species and of the mitochondrial isoform from Arabidopsis. Guided by modelling, we identified residues essential for functional discrimination of the differently located isoforms
to be located almost exclusively on the convex surface of the 3-TPR domain. The only exception is at568Ser/ps557Met, which is positioned in the ligand-binding groove. The functional implications of the homology models are discussed.
Figure Motion contained within the 2nd eigenvector of the Calpha covariance matrix of the 3-TPR domain of atToc64-V indicated by
a porcupine plot
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
10.
Muñoz-Muriedas J Barril X López JM Orozco M Luque FJ 《Journal of molecular modeling》2007,13(2):357-365
We investigate the changes in the solvation properties of the natural nucleic acid bases due to the formation of the canonical
Watson–Crick hydrogen-bonded complexes. To this end, the changes in the free energy of solvation of the bases induced upon
hydrogen-bonded dimerization are analyzed by means of the hydrophobic similarity index, which relies on the atomic contributions
to the free energy of solvation determined by the partitioning method implemented in the framework of the MST continuum model.
Such an index is also used to examine the hydrophobic similarity between the canonical nucleic acid bases and a series of
highly apolar analogues, which have been designed as potential candidates to expand the genetic alphabet. The ability of these
analogues to be incorporated into modified DNA duplexes can be related to the large reduction in the hydrophilicity of the
natural bases upon formation of the canonical hydrogen-bonded dimers. The results illustrate the suitability of the hydrophobic
similarity index to rationalize the role played by solvation in molecular recognition.
Proceedings of “Modeling Interactions in Biomolecules II”, Prague, September 5th–9th, 2005. 相似文献
11.
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
12.
Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical
trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745–749, 2002) have found a ligand NU6102, which has
a high affinity with cyclin-dependent kinase 2 (K
i
=6 nM) but a low affinity with cyclin-dependent kinase 4 (K
i
=1,600 nM). To understand the selectivity, we use homology modeling, molecular docking, molecular dynamics and free-energy
calculations to analyze the interactions. A rational 3D model of the Cdk4–NU6102 complex is built. Asp86 is a key residue
that recognizes NU6102 more effectively with Cdk2 rather than Cdk4. Good binding free energies are obtained. Energetic analysis
reveals that van der Waals interaction and nonpolar contributions to solvent are favorable in the formation of complexes and
the sulfonamide group of the ligand plays a crucial role for binding selectivity between Cdk2 and Cdk4.
Figure Two-dimensional representative for the interacting model of NU6102 complexed with the Cdk4 from a predicted structure by
LIGPLOT.
相似文献
13.
English NJ 《Journal of molecular modeling》2007,13(10):1081-1097
The linear interaction energy (LIE) approach has been applied to estimate the binding free energies of representative sets
of HIV-1 RT and β-Secretase inhibitors, using both molecular dynamics (MD) and tethered energy minimization sampling protocols
with the OPLS-AA potential, using a range of solvation methodologies. Generalized Born (GB), ‘shell’ and periodic boundary
condition (PBC) solvation were used, the latter with reaction field (RF) electrostatics. Poisson-Boltzmann (PB) and GB continuum
electrostatics schemes were applied to the simulation trajectories for each solvation type to estimate the electrostatic ligand-water
interaction energy in both the free and bound states. Reasonable agreement of the LIE predictions was obtained with respect
to experimental binding free energy estimates for both systems: for instance, ‘PB’ fits on MD trajectories carried out with
PBC solvation and RF electrostatics led to models with standard errors of 1.11 and 1.03 kcal mol−1 and coefficients of determination, r
2 of 0.76 and 0.75 for the HIV-1 RT and β-Secretase sets. However, it was also found that results from MD sampling using PBC
solvation provided only slightly better fits than from simulations using shell or Born solvation or tethered energy minimization
sampling.
Figure Evolution of the running averages for compound H11 (binding to HIV-1RT) of the bound state ligand-water and ligand-protein
interaction energies. The ligand-water electrostatic terms are twice the corresponding GB and PB electrostatic solvation free
energies. The ligand-receptor van der Waals and Coulombic interaction energies are also shown, in addition to the ligand-water
van der Waals interaction term. The terms were calculated (without application of a cut-off) from a trajectory sampled under
PBC solvation with reaction field electrostatics
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
14.
Fábio Alberto de Molfetta Renato Ferreira de Freitas Albérico Borges Ferreira da Silva Carlos Alberto Montanari 《Journal of molecular modeling》2009,15(10):1175-1184
In this work, two different docking programs were used, AutoDock and FlexX, which use different types of scoring functions
and searching methods. The docking poses of all quinone compounds studied stayed in the same region in the trypanothione reductase.
This region is a hydrophobic pocket near to Phe396, Pro398 and Leu399 amino acid residues. The compounds studied displays
a higher affinity in trypanothione reductase (TR) than glutathione reductase (GR), since only two out of 28 quinone compounds
presented more favorable docking energy in the site of human enzyme. The interaction of quinone compounds with the TR enzyme
is in agreement with other studies, which showed different binding sites from the ones formed by cysteines 52 and 58. To verify
the results obtained by docking, we carried out a molecular dynamics simulation with the compounds that presented the highest
and lowest docking energies. The results showed that the root mean square deviation (RMSD) between the initial and final pose were very small. In addition, the hydrogen bond pattern was conserved along the
simulation. In the parasite enzyme, the amino acid residues Leu399, Met400 and Lys402 are replaced in the human enzyme by
Met406, Tyr407 and Ala409, respectively. In view of the fact that Leu399 is an amino acid of the Z site, this difference could
be explored to design selective inhibitors of TR.
Docking and molecular dynamics simulation of genuine compounds with trypanocidal activity 相似文献
15.
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
16.
Shaikh AR Broclawik E Tsuboi H Koyama M Endou A Takaba H Kubo M Del Carpio CA Miyamoto A 《Journal of molecular modeling》2007,13(6-7):851-860
The metabolism mechanism of (S)-N-[1-(3-morpholin-4ylphenyl)ethyl]-3-phenylacrylamide, mediated by CYP3A4 Cytochrome has been
investigated by density functional QM calculations aided with molecular mechanics/molecular dynamics simulations. Two different
orientations of phenyl ring for substrate approach toward oxyferryl center, imposing two subsequent rearrangement pathways
have been investigated. Starting from σ-complex in perpendicular orientation enzymatic mechanism involves consecutive proton
shuttle intermediate, which further leads to the formation of alcohol and ketone. Parallel conformation leads solely to ketone
product by 1,2 hydride shift. Although parallel and perpendicular σ-complexes are energetically equivalent both for the gas
phase or PCM solvent model, molecular dynamics studies in full CYP3A4 environment show that perpendicular conformation of
the σ-complex should be privileged, stabilized by hydrophobic interactions of phenylacrylamide chain. After assessing probability
of the two conformations we postulate that the alcohol, accessible with the lowest energy barriers should be the major metabolite
for studied substrate and CYP3A4 enzyme.
Figure Orientation of phenyl ring towards porphyrin plane selected by substrate interaction with enzymatic cavity channels enzymatic
reaction 相似文献
17.
In this study, we performed a molecular docking and dynamics simulation for a benzoxazinone–human oxytocin receptor system to determine the possible hydrophobic and electrostatic interaction points in the dynamic complex. After the homology modeling, the ligand was docked into the putative active using AutoDock 3.05. After the application of energetic and structural filters, the complexes obtained were further refined with a simulated annealing protocol (AMBER8) to remove steric clashes. Three complexes were selected for subjection to the molecular dynamics simulation (5 ns), and the results on the occurrence of average anchor points showed a stable complex between the benzoxazinone derivative and the receptor. The complex could be used as a good starting point for further analysis with site-directed mutagenesis, or further computational research.
Figure The location of the ligands (complex B – blue; complex E – red; and complex F –
green) in the transmembrane regions (TM1 – red; TM2 – blue; TM3 – yellow; TM4
– purple; TM5 – orange; TM6 – cyan; TM7 – pink) of the hOTR. For clarity, the EC
and IC loops are not shown
Electronic Supplementary Material Supplementary material is available at 相似文献
18.
This work presents new developments of the moving-domain QM/MM (MoD-QM/MM) method for modeling protein electrostatic potentials.
The underlying goal of the method is to map the electronic density of a specific protein configuration into a point-charge
distribution. Important modifications of the general strategy of the MoD-QM/MM method involve new partitioning and fitting
schemes and the incorporation of dynamic effects via a single-step free energy perturbation approach (FEP). Selection of moderately
sized QM domains partitioned between and C (from C=O), with incorporation of delocalization of electrons over neighboring domains, results in a marked improvement
of the calculated molecular electrostatic potential (MEP). More importantly, we show that the evaluation of the electrostatic
potential can be carried out on a dynamic framework by evaluating the free energy difference between a non-polarized MEP and
a polarized MEP. A simplified form of the potassium ion channel protein Gramicidin-A from Bacillus brevis is used as the model system for the calculation of MEP.
Figure Schematic representation of the Moving Domain QM/MM method 相似文献
19.
Semiempirical molecular orbital theory has been used for a systematic scan of the binding positions for a Mg2+ ion with 5a,6–anhydrotetracycline taking both conformational flexibility and possible different tautomeric forms into account. The magnesium ion has been calculated alone and with four or five complexed water molecules in order to simulate the experimental situation more closely. The results are analyzed by comparing the behavior of the title compound with that of tetracycline itself and possible causes for the stronger induction of the Tetracycline Receptor (TetR) by 5a,6–anhydrotetracycline than by tetracycline are considered.
Energetically favored 3D -structure of the zwitteranionic 5a,6-anhydrotetracycline magnesium complex in solution
Electronic Supplementary Material Supplementary material is available for this article at 相似文献
20.
William N. Setzer 《Journal of molecular modeling》2009,15(2):197-201
Quantum chemical calculations at the B3LYP/6-31G* level of theory have been carried out on 20 celastroid triterpenoids to
obtain a set of molecular electronic properties and to correlate these with cytotoxic activities. The cytotoxic activities
of these compounds can be roughly correlated with electronic effects related to nucleophilic addition to C(6) of the compounds:
The energies of the frontier molecular orbitals (E
HOMO and E
LUMO), the HOMO-LUMO energy gap, the dipole moment, the charge on C(6), and the electrophilicity on C(6).
Figure LUMO of Pristimerin. 相似文献