988 research outputs found
How Accurate Are QM/MM Models?
No full textDespite the success and widespread use of QM/MM methods in modeling (bio)chemically important processes, their accuracy is still not well understood. A key reason is because these methods are ultimately approximations to direct QM calculations of very large systems, which are impractical to perform in most cases. We highlight recent progress toward the development of realistic model systems where it is possible to obtain full QM reference data to directly and systematically evaluate the effectiveness of different QM/MM generation schemes. These model systems are highly flexible and can be tailored to probe the sensitivity of a QM/MM model to different reaction types and simulation parameters such as pairing of QM and MM potentials, QM region size, and composition. It is envisaged that this strategy could be used to directly validate different QM/MM generation schemes and spur the development of more robust models in the future
A Highly Selective Rasorber With Ultraminiaturized Unit Based on Interdigitated 2.5-D Parallel Resonator
No full textA high selectivity frequency selective rasorber (FSR) with an ultraminiaturized unit based on 2.5 dimensional (2.5-D) parallel resonator (PR), exhibiting low insertion loss passband between two absorption bands, is investigated. The lossy unit is realized by inserting a 2.5-D strip-type PR structure into the center of each side of the metal square ring and loaded with resistors connected at the four corners. The novel 2.5-D PR consists of interdigitated capacitors and strip metal wire connecting the other side of the lossy layer obtained by using metallized vias. The 2.5-D PR can effectively alleviate the congestion of the single-sided structures and achieve a high degree of miniaturization by means of tortuous extension inductance structure; as an additional feature, the values of L and C can be independently adjusted to determine the passband frequency allowing to provide additional degree of freedom to the design. An equivalent circuit model is proposed to analyze its operating principle. The dimensions of the miniaturized unit are (being the free space wavelength at the passband). A transmission window with low insertion loss of 0.125 dB is obtained at 4.65 GHz under normal incidence. The fractional bandwidth for -10 dB reflection is about 96%. The miniaturized FSR satisfies the characteristic of polarization insensitivity (TE and TM) and angular insensitivity (up to 45 degrees). A prototype of miniaturized FSR has been manufactured and measured, showing a reasonable agreement with simulations
QM guided computational enzyme design
No full textPT3 is a redesigned adenosine deaminase that could catalyze the hydrolysis of organophosphate. In this present work, we evaluate the impact of previous designed mutations by investigating the mechanism of PT3. We started from the high-resolution crystal structure and truncated the active site residues as the QM model. Then the potential surface of the reaction was discovered by locating the transition states and intermediates along the reaction path with QM method B3LYP. The results showed a similar energy profile compared to natural phosphotriesterase and the nucleophilic attack turned out to be the rate-limiting step. The impact of a single mutation V218F that leaded to 20-fold increase in the catalytic rate kcat was rationalized by including this residue in QM model and a 5.0 kcal/mol difference of the reaction barrier was discovered. Then with the rationalized model, we performed a low-level QM calculation with key bond lengths fixed at a value from high-level QM results. The barrier difference of V218F changed to 3.6kcal/mol, which was still consistent with experimental results while the computation time was cut half. With this fast computational setting, we are able to analyze more mutations of their impact on the reaction barrier quantum mechanically.M.S.Includes bibliographical referencesby Beidi L
How Accurate Are QM/MM Models?
No full textDespite the success and widespread use of QM/MM methods in modeling (bio)chemically important processes, their accuracy is still not well understood. A key reason is because these methods are ultimately approximations to direct QM calculations of very large systems, which are impractical to perform in most cases. We highlight recent progress toward the development of realistic model systems where it is possible to obtain full QM reference data to directly and systematically evaluate the effectiveness of different QM/MM generation schemes. These model systems are highly flexible and can be tailored to probe the sensitivity of a QM/MM model to different reaction types and simulation parameters such as pairing of QM and MM potentials, QM region size, and composition. It is envisaged that this strategy could be used to directly validate different QM/MM generation schemes and spur the development of more robust models in the future.</p
The Effects of Conformational Sampling and QM Region Size in QM/MM Simulations: An Adaptive QM/MM Study With Model Systems
No full textMolecular properties in combined quantum mechanics and molecular mechanics (QM/MM) simulations have been shown to be dependent on the size of the quantum mechanical (QM) region and the amount of conformational sampling. Previous studies have largely focused on enzymatic systems, which have made it difficult to distinguish the effects of QM region size and conformational sampling from other factors including QM-MM boundary artifacts and the boundary effects. This study uses the difference-based adaptive solvation QM/MM method to investigate the tautomerization reactions of alanine and aspartate in explicit solvent. The choice of computationally tractable systems enables the decoupling of QM region size effects from other factors and a direct comparison of free energy surfaces with potential energy surfaces (PESs). The results show that (1) it is crucial to properly account for thermal fluctuations along the reaction pathways, and (2) free energy surfaces converge rapidly with increasing QM region size, whereas charge transfer requires a slightly larger QM region to achieve convergence. These findings are expected to guide future studies of enzymatic systems and other complex systems where QM/MM methods are applied.</p
QM/MM Modeling of enantioselective pybox-ruthenium- and box-copper-catalyzed cyclopropanation reactions: Scope, performance, and applications to ligand design
No full text10 pages, 7 tables, 9 figures, 2 schemes.-- Supporting information for this article is available on http://www.chemeurj.org/ or from the author.-- In memory of Professor Marcial Moreno-Mañas.An extensive comparison of full-QM (B3LYP) and QM/MM (B3LYP:UFF) levels of theory has been made for two enantioselective catalytic systems, namely, Pybox-Ru and Box-Cu complexes, in the cyclopropanation of alkenes (ethylene and styrene) with methyl diazoacetate. The geometries of the key reaction intermediates and transition structures calculated at the QM/MM level are generally in satisfactory agreement with full-QM calculated geometries. More importantly, the relative energies calculated at the QM/MM level are in good agreement with those calculated at the full-QM level in all cases. Furthermore, the QM/MM energies are often in better agreement with the stereoselectivity experimentally observed, and this suggests that QM/MM calculations can be superior to full-QM calculations when subtle differences in inter- and intramolecular interactions are important in determining the selectivity, as is the case in enantioselective catalysis. The predictive value of the model presented is validated by the explanation of the unusual enantioselectivity behavior exhibited by a new bis-oxazoline ligand, the stereogenic centers of which are quaternary carbon atoms.This work was made possible by the financial support of the Gobierno de
Navarra (project GN05)and the Ministerio de Educación y Ciencia
(project CTQ2005-08016). I.V. and G.J.-O. respectively thank the Ministerio
de Educación y Ciencia and Universidad de La Rioja for grants.Peer reviewe
QM/MM and Classical Molecular Dynamics Simulation of Histidine-Tagged Peptide Immobilization on Nickel Surface
No full textThe hybrid quantum mechanics (QM) and molecular mechanics (MM) method is employed to simulate the His-tagged peptide adsorption
to ionized region of nickel surface. Based on the previous experiments, the peptide interaction with one Ni ion is considered. In the QM/MM
calculation, the imidazoles on the side chain of the peptide and the metal ion with several neighboring water molecules are treated as QM
part calculated by “GAMESS”, and the rest atoms are treated as MM part calculated by “TINKER”. The integrated molecular orbital/molecular
mechanics (IMOMM) method is used to deal with theQMpart with the transitional metal. By using the QM/MM method, we optimize the structure
of the synthetic peptide chelating with a Ni ion. Different chelate structures are considered. The geometry parameters of the QM subsystem we
obtained by QM/MM calculation are consistent with the available experimental results. We also perform a classical molecular dynamics (MD)
simulation with the experimental parameters for the synthetic peptide adsorption on a neutral Ni(1 0 0) surface. We find that half of the His-tags
are almost parallel with the substrate, which enhance the binding strength. Peeling of the peptide from the Ni substrate is simulated in the aqueous
solvent and in vacuum, respectively. The critical peeling forces in the two environments are obtained. The results show that the imidazole rings are
attached to the substrate more tightly than other bases in this peptide
Protein-ligand binding affinities from large-scale quantum mechanical simulations
No full textThe accurate prediction of protein-drug binding affinities is a major aim of computational drug optimisation and development. A quantitative measure of binding affinity is provided by the free energy of binding, and such calculations typically require extensive configurational sampling of entities such as proteins with thousands of atoms. Current binding free energy methods use force fields to perform the configurational sampling and to compute interaction energies. Due to the empirical nature of force fields and the neglect of electrons, electron polarisation and charge transfer are not accounted for explicitly. This can limit the accuracy with which interactions are calculated and consequently the free energies obtained. Ideally ab initio quantum chemistry approaches should be used as these explicitly include the electrons. However, conventional ab initio approaches are not suitable due to their prohibitively high computational cost and unfavourable scaling.In this thesis we use large-scale ab initio quantum chemistry calculations within the Density Functional Theory (DFT) method to address the above mentioned limitations of force fields. To obtain quantitative results with ab initio approaches it is important to converge the calculations with the size of the basis set. For this reason we have used the ONETEP program, which is capable of linear-scaling DFT with near-complete basis set accuracy.A well known binding free energy approach is the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA), which obtains free energies from evaluation of the energy of configurations in an implicit solvent model. We present the first application of a “QM-PBSA” approach to a protein-ligand system containing over 2600 atoms. In this QM-PBSA approach the energies of the configurations in vacuum are evaluated with ONETEP. The solvation energies were also obtained with ONETEP using a minimal parameter implicit solvent model within the self-consistent calculation. Large-scale DFT calculations were also applied within a more theoretically rigorous free energy approach which can, in principle, obtain the full entropic contributions to free energy change. The method performs a mutation from a molecular mechanical (MM) description to an quantum mechanical (QM) description of a system. As a result a QM correction is added to the relative binding free energy obtained from a thermodynamic integration calculation within the MM description.This approach was combined with an electrostatic embedding model within ONETEP and used to calculate the hydration energies of small molecules. As well as the computation of more accurate energies, large-scale DFT calculation compute the electron density of the entire system. Using electron density analysis approaches, such as the Hirshfeld density analysis, in combination with energy decomposition approaches, such as a second order perturbation estimate of natural bond orbital interactions, both qualitative and quantitative understandings can be gained into the contributions of particular chemical functional groups that define protein-ligand interactions. These two approaches where applied to study complexes of the Phosphodiesterase type 5 protein and used to rank ligand binding affinities that agree well with then experimentally observed trends
Tailoring Parameters for QM/MM Simulations: Accurate Modeling of Adsorption and Catalysis in Zirconium-Based Metal-Organic Frameworks
No full textQuantum mechanics/molecular mechanics (QM/MM) simulations offer an efficient way to model reactions occurring in complex environments. This study introduces a specialized set of charge and Lennard-Jones parameters tailored for electrostatically embedded QM/MM calculations, aiming to accurately model both adsorption processes and catalytic reactions in zirconium-based metal-organic frameworks (Zr-MOFs). To validate our approach, we compare adsorption energies derived from QM/MM simulations against experimental results and Monte Carlo simulation outcomes. The developed parameters showcase the ability of QM/MM simulations to represent long-range electrostatic and van der Waals interactions faithfully. This capability is evidenced by the prediction of adsorption energies with a low root mean square error of 1.1 kcal/mol across a wide range of adsorbates. The practical applicability of our QM/MM model is further illustrated through the study of glucose isomerization and epimerization reactions catalyzed by two structurally distinct Zr-MOF catalysts, UiO-66 and MOF-808. Our QM/MM calculations closely align with experimental activation energies. Importantly, the parameter set introduced here is shown to be compatible with the widely used universal force field (UFF). Moreover, we thoroughly explore how the size of the cluster model and the choice of density functional theory (DFT) methodologies influence the simulation outcomes. This work provides an accurate and computationally efficient framework for modeling complex catalytic reactions within Zr-MOFs, contributing valuable insights into their mechanistic behaviors and facilitating further advancements in this dynamic area of research
Predicting Solvent Effects on SN2 Reaction Rates – Comparison of QM/MM, Implicit and MM Explicit Solvent Models
No full textSolvents are one of the key variables in the optimisation of a synthesis yield or properties of a synthesis product. In this paper, contemporary solvent models are applied to predict the rates of SN2 reactions in a range of aqueous and non-aqueous solvents. High-level CCSD(T)/CBS//M06-2X/6-31+G(d) gas phase energies were combined with solvation free energies from SMD, SM12 and ADF-COSMO-RS continuum solvent models as well as molecular mechanics (MM) explicit solvent models with different atomic charge schemes to predict the rate constants of three SN2 reactions in eight protic and aprotic solvents. It is revealed that popular solvent models struggle to predict their rate constants to within 3 log units of experimental values and deviations as large as 7.6 log units were observed. Amongst the implicit solvent models, the ADF-COSMO-RS model performed the best in predicting absolute rate constants with an average accuracy of 1.5 log units while the SM12 and CGenFF/TIP3P MM explicit solvent models were most accurate in the prediction of relative rate constants in different solvents due to systematic error cancellation. Free energy barriers obtained from umbrella sampling with explicit solvent QM/MM simulations led to excellent agreement with experiment provided that a validated level of theory is used to treat the QM region
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