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At least 19 recordsLinked to original sources
PubMed2002

Role of protein flexibility in enzymatic catalysis: quantum mechanical-molecular mechanical study of the deacylation reaction in class A beta-lactamases.

We present a theoretical study of a mechanism for the hydrolysis of the acyl-enzyme complex formed by a class A beta-lactamase (TEM1) and an antibiotic (penicillanate), as a part of the process of antibiotic's inactivation by this type of enzymes. In the presented mechanism the carboxylate group of a particular residue (Glu166) activates a water molecule, accepting one of its protons, and afterward transfers this proton directly to the acylated serine residue (Ser70). In our study we employed a quantum mechanics (AM1)-molecular mechanics partition scheme (QM/MM) where all the atoms of the system were allowed to relax. For this purpose we used the GRACE procedure in which part of the system is used to define the Hessian matrix while the rest is relaxed at each step of the stationary structures search. By use of this computational scheme, the hydrolysis of the acyl-enzyme is described as a three-step process: The first step corresponds to the proton transfer from the hydrolytic water molecule to the carboxylate group of Glu166 and the subsequent formation of a tetrahedral adduct as a consequence of the attack of this activated water molecule to the carbonyl carbon atom of the beta-lactam. In the second step, the acyl-enzyme bond is broken, obtaining a negatively charged Ser70. In the last step this residue is protonated by means of a direct proton transfer from Glu166. The large mobility of Glu166, a residue that is placed in a Ohms-loop, is essential to facilitate this mechanism. The geometry of the acyl-enzyme complex shows a large distance between Glu166 and Ser70 and thus, if protein coordinates were kept frozen during the reaction path, it would be difficult to get a direct proton transfer between these two residues. This computational study shows how a flexible treatment suggests the feasibility of a mechanism that could have been discounted on the basis of crystallographic positions.

Acylation↗
PubMed2005

A regularized and renormalized electrostatic coupling Hamiltonian for hybrid quantum-mechanical-molecular-mechanical calculations.

We describe a regularized and renormalized electrostatic coupling Hamiltonian for hybrid quantum-mechanical (QM)-molecular-mechanical (MM) calculations. To remedy the nonphysical QM/MM Coulomb interaction at short distances arising from a point electrostatic potential (ESP) charge of the MM atom and also to accommodate the effect of polarized MM atom in the coupling Hamiltonian, we propose a partial-wave expansion of the ESP charge and describe the effect of a s-wave expansion, extended over the covalent radius r(c), of the MM atom. The resulting potential describes that, at short distances, large scale cancellation of Coulomb interaction arises intrinsically from the localized expansion of the MM point charge and the potential self-consistently reduces to 1r(c) at zero distance providing a renormalization to the Coulomb energy near interatomic separations. Employing this renormalized Hamiltonian, we developed an interface between the Car-Parrinello molecular-dynamics program and the classical molecular-dynamics simulation program Groningen machine for chemical simulations. With this hybrid code we performed QM/MM calculations on water dimer, imidazole carbon monoxide (CO) complex, and imidazole-heme-CO complex with CO interacting with another imidazole. The QM/MM results are in excellent agreement with experimental data for the geometry of these complexes and other computational data found in literature.

Carbon Monoxide↗
PubMed2004

Reaction path potential for complex systems derived from combined ab initio quantum mechanical and molecular mechanical calculations.

Combined ab initio quantum mechanical and molecular mechanical calculations have been widely used for modeling chemical reactions in complex systems such as enzymes, with most applications being based on the determination of a minimum energy path connecting the reactant through the transition state to the product in the enzyme environment. However, statistical mechanics sampling and reaction dynamics calculations with a combined ab initio quantum mechanical (QM) and molecular mechanical (MM) potential are still not feasible because of the computational costs associated mainly with the ab initio quantum mechanical calculations for the QM subsystem. To address this issue, a reaction path potential energy surface is developed here for statistical mechanics and dynamics simulation of chemical reactions in enzymes and other complex systems. The reaction path potential follows the ideas from the reaction path Hamiltonian of Miller, Handy and Adams for gas phase chemical reactions but is designed specifically for large systems that are described with combined ab initio quantum mechanical and molecular mechanical methods. The reaction path potential is an analytical energy expression of the combined quantum mechanical and molecular mechanical potential energy along the minimum energy path. An expansion around the minimum energy path is made in both the nuclear and the electronic degrees of freedom for the QM subsystem internal energy, while the energy of the subsystem described with MM remains unchanged from that in the combined quantum mechanical and molecular mechanical expression and the electrostatic interaction between the QM and MM subsystems is described as the interaction of the MM charges with the QM charges. The QM charges are polarizable in response to the changes in both the MM and the QM degrees of freedom through a new response kernel developed in the present work. The input data for constructing the reaction path potential are energies, vibrational frequencies, and electron density response properties of the QM subsystem along the minimum energy path, all of which can be obtained from the combined quantum mechanical and molecular mechanical calculations. Once constructed, it costs much less for its evaluation. Thus, the reaction path potential provides a potential energy surface for rigorous statistical mechanics and reaction dynamics calculations of complex systems. As an example, the method is applied to the statistical mechanical calculations for the potential of mean force of the chemical reaction in triosephosphate isomerase.

Binding Sites↗
PubMed2004

Monosialogangliosides and their interaction with cholera toxin - investigation by molecular modeling and molecular mechanics.

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface monosialogangliosides (GM3, GM2 and GM1) in aqueous environment. Water mediated hydrogen bonding network plays a significant role in the structural stabilization of GM3, GM2 and GM1. The spatial flexibility of NeuNAc of gangliosides at the binding site of cholera toxin reveals a limited allowed eulerian space of 2.4% with a much less allowed eulerian space (1.4%) for external galactose of GM1. The molecular mechanics of monosialoganglioside-cholera toxin complex reveals that cholera toxin can accommodate the monosialogangliosides in three different modes. Direct and water mediated hydrogen bonding interactions stabilize these binding modes and play an essential role in defining the order of specificity for different monosialogangliosides towards cholera toxin. This study identifies the NeuNAc binding site as a site for design of inhibitors that can restrict the pathogenic activity of cholera toxin.

Carbohydrate Conformation↗
PubMed2004

Disialogangliosides and their interaction with cholera toxin - investigation by molecular modeling, molecular mechanics and molecular dynamics.

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface disialogangliosides (GD1A, GD1B and GD3) in aqueous environment. The molecular mechanics calculation reveals that water mediated hydrogen bonding network plays a significant role in the structural stabilization of GD1A, GD1B and GD3. These water mediated hydrogen bonds not only exist between neighboring residues but also exist between residues that are separated by 2 to 3 residues in between. The conformational energy difference between different conformational states of gangliosides correlates very well with the number of water mediated and direct hydrogen bonds. The spatial flexibility of NeuNAc of gangliosides at the binding site of cholera toxin is worked out. The NeuNAc has a limited allowed eulerian space at the binding site of Cholera Toxin (2.4%). The molecular modeling, molecular mechanics and molecular dynamics of disialoganglioside-cholera toxin complex reveal that cholera toxin can accommodate the disialoganglioside GD1A in three different modes. A single mode of binding is permissible for GD1B and GD3. Direct and water mediated hydrogen bonding interactions stabilizes these binding modes and play an essential role in defining the order of specificity for different disialogangliosides towards cholera toxin. This study not only provides models for the disialoganglioside-cholera toxin complexes but also identifies the NeuNAc binding site as a site for design of inhibitors that can restrict the pathogenic activity of cholera toxin.

Binding Sites↗
PubMed2006

Conformations of higher gangliosides and their binding with cholera toxin - investigation by molecular modeling, molecular mechanics, and molecular dynamics.

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface higher gangliosides (GT1A and GT1B) and their interaction with Cholera Toxin. The water mediated hydrogen bonding network exists between sugar residues in gangliosides. An integrated molecular modeling, molecular mechanics, and molecular dynamics calculation of cholera toxin complexed with GT1A and GT1B reveal that, the active site of cholera toxin can accommodate these higher gangliosides. Direct and water mediated hydrogen bonding interactions stabilize these binding modes and play an essential role in defining the order of specificity for different higher ganglioside towards cholera toxin. This study identifies that the binding site of cholera toxin is shallow and can accommodate a maximum of two NeuNAc residues. The NeuNAc binding site of cholera toxin may be crucial for the design of inhibitors that can prevent the infection of cholera.

Binding Sites↗
PubMed2005

Selectivity of bis(calix[4]diquinone) ionophores towards metal ions in solvent dimethylsulfoxide: a molecular mechanics and molecular dynamics study.

Molecular modelling studies have been carried out on two bis(calix[4]diquinone) ionophores, each created from two (calix[4]diquinone)arenes bridged at their bottom rims via alkyl chains (CH(2))(n), 1: n = 3, 2; n = 4, in order to understand the reported selectivity of these ligands towards different sized metal ions such as Na(+), K(+), Rb(+), and Cs(+) in dmso solution. Conformational analyses have been carried out which show that in the lowest energy conformations of the two macrocycles, the individual calix[4]diquinones exhibit a combination of partial cone, 1,3-alternate and cone conformations. The interactions of these alkali metals with the macrocycles have been studied in the gas phase and in a periodic box of solvent dmso by molecular mechanics and molecular dynamics calculations. Molecular mechanics calculations have been carried out on the mode of entry of the ions into the macrocycles and suggest that this is likely to occur from the side of the central cavity, rather than through the main axis of the calix[4]diquinones. There are energy barriers of ca. 19 kcal mol(-1) for this entry path in the gas phase, but in solution no energy barrier is found. Molecular dynamics simulations show that in both 1 and 2, though particularly in the latter macrocycle, one or two solvent molecules are bonded to the metal throughout the course of the simulation, often to the exclusion of one or more of the ether oxygen atoms. By contrast the carbonyl oxygen atoms remain bonded to the metal atoms throughout with bond lengths that remain significantly less than those to the ether oxygen atoms. Free energy perturbation studies have been carried out in dmso and indicate that for 1, the selectivity follows the order Rb(+) approximately K(+) > Cs(+) >> Na(+), which is partially in agreement with the experimental results. The energy differences are small and indeed the ratio between stability constants found for Cs(+) and K(+) complexes is only 0.60, showing that has only a slight preference for K(+). For the larger receptor , which is better suited to metal complexation, the binding affinity follows the pattern Cs(+) >> Rb(+) >> K(+) >> Na(+), with energy differences of 5.75, 2.61, 2.78 kcal mol(-1) which is perfectly consistent with experimental results.

Calixarenes↗
PubMed1988

Investigation of the substrate binding and phosphate transfer in adenylate kinase by molecular mechanics.

Molecular mechanics calculations of adenylate kinase (ADK) complexed with ATP, AMP, and Mg2+ have been carried out with three different model-built geometries. The lowest energy structure is that inferred from the X-ray structure, but such a geometry is not as consistent with the inference of an NOE contact between His36 and the ATP C2-H proton as the model of the second lowest energy. We have used the latter structure as a basis for modeling the reaction AMP + ATP----2ADP in the presence of Mg2+ and ADK. The key residues in the enzyme that stabilize the intermediate points in the above reaction are Arg44 and Arg97. This is the first clear picture of how an enzyme can catalyse a reaction which is electrostatically unfavorable.

Adenylate Kinase↗
PubMed2001

[Morphogenesis and pattering in hydra. II. Molecular mechanisms].

Molecular mechanisms of morphogenesis and pattern formation have been extensively studied during the last decades. Recent data suggest that many of the signalling systems as well as transcription factors governing embryonic development in the higher animals have been already established in the lower Metazoa. This review summarizes the information on the roles of peptide systems, signal transduction cascades, transcriptional activators and the extracellular matrix-processing enzymes in the developmental processes in Hydra.

Animals↗
PubMed2005

Structures and stabilities of diacetylene-expanded polyhedranes by quantum mechanics and molecular mechanics.

The structures, heats of formation, and strain energies of diacetylene (buta-1,3-diynediyl) expanded molecules have been computed with ab initio and molecular mechanics calculations. Expanded cubane, prismane, tetrahedrane, and expanded monocyclics and bicyclics were optimized at the HF/6-31G(d) and B3LYP/6-31G(d) levels. The heats of formation of these systems were obtained from isodesmic equations at the HF/6-31G(d) level. Heats of formation were also calculated from Benson group equivalents. The strain energies of these expanded molecules were estimated by several independent methods. An adapted MM3 molecular mechanics force field, specifically parametrized to treat conjugated acetylene units, was employed for one measure of strain energy and as an additional method for structural analysis. Expanded dodecahedrane and icosahedrane were calculated by this method. Expanded molecules were considered structurally in the context of their potential material applications.

Acetylene↗
PubMedDate not supplied

Combined quantum mechanical and molecular mechanical reaction pathway calculation for aromatic hydroxylation by p-hydroxybenzoate-3-hydroxylase.

The reaction pathway for the aromatic 3-hydroxylation of p-hydroxybenzoate by the reactive C4a-hydroperoxyflavin cofactor intermediate in p-hydroxybenzoate hydroxylase (PHBH) has been investigated by a combined quantum mechanical and molecular mechanical (QM/MM) method. A structural model for the C4a-hydroperoxyflavin intermediate in the PHBH reaction cycle was built on the basis of the crystal structure coordinates of the enzyme-substrate complex. A reaction pathway for the subsequent hydroxylation step was calculated by imposing a reaction coordinate that involves cleavage of the peroxide oxygen-oxygen bond and formation of the carbon-oxygen bond between the C3 atom of the substrate and the distal oxygen of the peroxide moiety of the cofactor. The geometric changes and the Mulliken charge distributions along the calculated reaction pathway are in line with an electrophilic aromatic substitution type of mechanism. The energy barrier of the calculated reaction is considerably lower when the substrate hydroxyl moiety is deprotonated, in comparison with the barrier found with a protonated hydroxyl moiety. This effect of the protonation state of the substrate on the calculated energy barrier supports experimental observations that deprotonation is required for hydroxylation of the substrate. A notable event in the calculated reaction pathway is a lengthening of the peroxide oxygen-oxygen bond at an intermediate stage. Further analysis of the reaction pathway indicates that this oxygen-oxygen bond elongation is accompanied by an increase in electrophilic reactivity on the distal oxygen of the peroxide moiety, which may assist the C-O bond formation in the reaction of the C4a-hydroperoxyflavin intermediate with the substrate. Analysis of the effect of individual active site residues on the reaction reveals a specific transition state stabilization by the backbone carbonyl moiety of Pro293. The crystal water 717 appears to drive the hydroxylation step through a stabilizing hydrogen bond interaction to the proximal oxygen of the C4a-hydroperoxyflavin intermediate, which increases in strength as the hydroperoxyflavin cofactor converts to the anionic (deprotonated) hydroxyflavin.

4-Hydroxybenzoate-3-Monooxygenase↗
PubMed2005

Redistributed charge and dipole schemes for combined quantum mechanical and molecular mechanical calculations.

Special care is needed in carrying out combined quantum mechanical and molecular mechanical (QM/MM) calculations if the QM/MM boundary passes through a covalent bond. The present paper discusses the importance of correctly handling the MM partial point charges at the QM/MM boundary, and in particular, it contributes in two aspects: (1) Two schemes, namely, the redistributed charge (RC) scheme and the redistributed charge and dipole (RCD) scheme, are introduced to handle link atoms in QM/MM calculations. In both schemes, the point charge at the MM boundary atom that is replaced by the link atom is redistributed to the midpoint of the bonds that connect the MM boundary atom and its neighboring MM atoms. These redistributed charges serve as classical mimics for the auxiliary orbitals associated with the MM host atom in the generalized hybrid orbital (GHO) method. In the RCD scheme, the dipoles of these bonds are preserved by further adjustment of the values of the redistributed charges. The treatments are justified as classical analogues of the QM description given by the GHO method. (2) The new methods are compared quantitatively to similar methods that were suggested by previous work, namely, a shifted-charge scheme and three eliminated-charge schemes. The comparisons were carried out for a series of molecules in terms of proton affinities and geometries. Point charges derived from various charge models were tested. The results demonstrate that it is critical to preserve charge and bond dipole and that it is important to use accurate MM point charges in QM/MM boundary treatments. The RCD scheme was further applied to study the H atom transfer reaction CH3 + CH3CH2CH2OH --> CH4 + CH2CH2CH2OH. Various QM levels of theory were tested to demonstrate the generality of the methodology. It is encouraging to find that the QM/MM calculations obtained a reaction energy, barrier height, saddle-point geometry, and imaginary frequency at the saddle point in quite good agreement with full QM calculations at the same level. Furthermore, analysis based on energy decomposition revealed the quantitatively similar interaction energies between the QM and the MM subsystems for the reactant, for the saddle point, and for the product. These interaction energies almost cancel each other energetically, resulting in negligibly small net effects on the reaction energy and barrier height. However, the charge distribution of the QM atoms is greatly affected by the polarization effect of the MM point charges. The QM/MM charge distribution agrees much better with full QM results than does the unpolarized charge distribution of the capped primary subsystem.

Chemistry, Physical↗
PubMed2000

Ligand binding inside the cavities of lacunar and saddle-shaped cyclidene complexes: molecular mechanics and molecular dynamics studies.

Cobalt(II) complexes with tetradentate macrocyclic cyclidene ligands are known to coordinate one additional axial base molecule, leaving the sixth vacant coordination site at the metal ion available for small ligand (e.g., O2) binding. Molecular mechanics and molecular dynamics simulations provide a microscopic view of 1-methylimidazole (MeIm) binding within the cavities of several lacunar (bridged) and saddle-shaped (unbridged) cyclidenes and uncover the roles of the bridges and the walls of the clefts in steric protection of the cobalt(II) coordination site. Short bridges (C3 and C6) prevent inside-the-cavity MeIm binding because of severe ligand distortions leading to high-energy penalties (58 and 25 kcal/mol, respectively), while long bridges (C8 and C12) flip away from the MeIm binding site, allowing for penalty-free MeIm inclusion. In the unbridged saddle-shaped complex, there is no energy difference between inside- and outside-the-cavity MeIm binding. The preferential existence of the coordinatively unsaturated, five-coordinate species Co(unbrCyc)(MeIm)2+ should therefore be explained by electronic, rather than steric, factors. Molecular dynamics and free energy simulations reveal the presence of a weak (ca. 4 kcal/mol in the gas phase and ca. 2 kcal/mol in methanol solution) noncovalent MeIm binding site at the entrance of the cleft of cobalt(II) unbridged cyclidene, at a distance of about 4 A from the metal ion. The macrocycle geometry remains undistorted at such large Co-N(MeIm) separations, while the cavity opens up by 0.9 A upon covalent MeIm binding (Co-N(MeIm) distance of 2 A). An increase in macrocycle strain energy upon MeIm inclusion is compensated by favorable nonbonded interactions between the incoming base and the walls of the unbridged cyclidene.

Journal Article↗
PubMed1996

Molecular structure, conformational analysis, and structure-activity studies of Dendrotoxin and its homologues using molecular mechanics and molecular dynamics techniques.

Three-dimensional structures of Dendrotoxin (DtX), Toxin-I (DpI), and Toxin-K (DpK) were determined using molecular mechanics and molecular dynamics techniques. The overall molecular conformation and protein folding of the three dendrotoxins are very similar to the published crystal structures of bovine pancreatic trypsin inhibitor (BPTI) and alpha-DtX. Major secondary structural regions of the dendrotoxins are stable without much fluctuation during the dynamics simulation; the regions corresponding to the turns and bends (rich in lysines and arginines) exhibit more fluctuations. The conformational angles and the C alpha...C alpha' distances of the three disulfides (in each of the dendrotoxins) are different from each other. Comparative model building studies, involving the dendrotoxins and the proteinases, reveal that the key interactions (observed in BPTI-trypsin complex) needed for anti-protease activity are absent due to structural differences between the dendrotoxins and BPTI at the anti-protease loop; this explains the inability of the dendrotoxins to inhibit proteinases. The model also suggests that the solvent-exposed beta-turn region, rich in lysines (residues 26-28), might bind directly to the extracellular anionic sites of the receptors (K+ channels) by ionic interactions. The strikingly homologous cysteine distribution (Cys-x-x-x-Cys) in DtX, DpI, and DpK, at the C-terminus, induces the occurrence of a characteristic conformational motif, consisting of an alpha-helix (in an amphiphilic environment) stabilized by two disulfides, one involving a cysteine at the beta-strand, and the other at the N-terminus. This amphiphilic secondary structural element seems to provide the rigid frame work needed for exposing the proposed active site region of the dendrotoxins to the anionic sites of the K+ channel receptors.

Amino Acid Sequence↗
PubMed2005

Microscopic and macroscopic polarization within a combined quantum mechanics and molecular mechanics model.

A polarizable quantum mechanics and molecular mechanics model has been extended to account for the difference between the macroscopic electric field and the actual electric field felt by the solute molecule. This enables the calculation of effective microscopic properties which can be related to macroscopic susceptibilities directly comparable with experimental results. By separating the discrete local field into two distinct contribution we define two different microscopic properties, the so-called solute and effective properties. The solute properties account for the pure solvent effects, i.e., effects even when the macroscopic electric field is zero, and the effective properties account for both the pure solvent effects and the effect from the induced dipoles in the solvent due to the macroscopic electric field. We present results for the linear and nonlinear polarizabilities of water and acetonitrile both in the gas phase and in the liquid phase. For all the properties we find that the pure solvent effect increases the properties whereas the induced electric field decreases the properties. Furthermore, we present results for the refractive index, third-harmonic generation (THG), and electric field induced second-harmonic generation (EFISH) for liquid water and acetonitrile. We find in general good agreement between the calculated and experimental results for the refractive index and the THG susceptibility. For the EFISH susceptibility, however, the difference between experiment and theory is larger since the orientational effect arising from the static electric field is not accurately described.

Journal Article↗
PubMed1998

Catalytic mechanism of aldose reductase studied by the combined potentials of quantum mechanics and molecular mechanics.

The catalytic reduction of D-glyceraldehyde to glycerol by aldose reductase has been investigated with the combined potentials of quantum mechanics (QM) and molecular mechanics (MM) to resolve the question of whether Tyr48 or His110 serves as the proton donor during catalysis. Site directed mutagenesis studies favor Tyr48 as the proton donor while the presence of a water channel linking the N delta 1 of His110 to the bulk solvent suggests that His110 is the proton donor. Utilizing the combined potentials of QM and MM, the binding mode of substrate D-glyceraldehyde was investigated by optimizing the local geometry of Asp43, Lys77, Tyr48, His110 and NADPH at the active site of aldose reductase. Reaction pathways for the reduction of D-glyceraldehyde to glycerol were then constructed by treating both Tyr48 and His110 as proton donors. Comparison of energetics obtained from the reaction pathways suggests His110 to be the proton donor. Based on these findings, a reduction mechanism of D-glyceraldehyde to glycerol is described.

Aldehyde Reductase↗
PubMed2001

alpha-, beta-, and gamma-Cyclodextrin dimers. Molecular modeling studies by molecular mechanics and molecular dynamics simulations.

The alpha-, beta-, and gamma-cyclodextrin (CyD) dimers have been studied by molecular mechanics (MM) and molecular dynamics (MD) calculations, and the relative stability of dimers and the involved molecular interactions have been determined. Three possible orientations were considered for the alpha-, beta-, and gamma-CyD dimers: the head-to-head, the head-to-tail, and the tail-to-tail. In vacuo MM calculations were used to obtain the most stable arrangements, and MD simulations were performed over all energy minima obtained for each dimer. Results from MD always show head-to-head orientation as the most stable as a result of the larger number of intermolecular hydrogen bonds present.

Journal Article↗
PubMed1992

Investigation of the inhibition pathway of glucosamine synthase by N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid by semiempirical quantum mechanical and molecular mechanics methods.

Glucosamine synthase (E.C. 2.6.1.16) is a promising target in antifungal drug design. It has been reported that its potent inhibitor, N3-(4-methoxyfumaroyl)-L-2,3-diaminopropanoic acid (FMDP), inactivates the enzyme by the Michael addition of the S-H group to the FMDP molecule followed by cyclisation reactions. In this study we have investigated, by means of semiempirical MNDO, PM3 and molecular mechanics methods, the energetics and kinetic possibility of the formation of various stereoisomers of the products of cyclisation of the Michael addition products detected experimentally. It was found that the substituted 1,4-thiazin-3-one can be formed in one step under alkaline conditions; the stereoisomers of this compound predicted to be the most stable on the basis of theoretical calculations are also the dominant ones in reality.

Calorimetry↗