Chemical theory and computation

This grant was $12500 for partial support of an international conference, Molecular Quantum Mechanics 2010, which was held on the campus of the University of California, Berkeley, from 24 to 29 May 2010. The conference involved more than 250 participants. The conference schedule ran from as early as 8:00 AM to as late as 10:30 PM at night, in order to accommodate six historical lectures, 16 plenary lectures, 42 invited talks and two very strong poster sessions containing 143 contributed posters. Since 1989, the Molecular Quantum Mechanics (MQM) series of international conferences has show- cased the frontiers of research in quantum chemistry with a strong focus on basic theory and algorithms, as well as highlights of topical applications. Both were strongly in evidence at MQM 2010. At the same time as embracing the future, the MQM conferences also honour the lifetime contributions of some of the most prominent scientists in the field of theoretical and computational quantum chemistry. MQM 2010 recognised the work of Prof. Henry F. ‘Fritz’ Schaefer of the Center for Computational Chemistry at the University of Georgia, who was previously on the faculty at Berkeley The travel of invited speakers was partially covered by sponsorships from Dell Computer, Hewlett-Packard, Journal of Chemical Theory and Computation, Virginia Tech College of Science, Molecular Physics, Q-Chem Inc and the American Institute of Physics. By contrast, the conference grant from the Department of Energy was used to provide fellowships and scholarships to enable graduate students and postdoctoral fellows to attend the meeting, and thereby broaden the participation of young scientists at a meeting where in the past most of the attendees have been more senior faculty researchers. We believe that we were very successful in this regard: 118 students and postdocs attended out of the total of 256 participants. In detail, the DOE sponsorship money was partially used for dormitory scholarships that covered the cost of shared accommodation for students and postdocs at Berkeley dormitories. This covered the $200-$305 cost of a shared room for the 5-day duration of the conference. The only condition of these scholarships was that the awardee must present a poster at the meeting. Approximately $7565 was spent for these dormitory scholarships. The remaining expenditures of $4800 was used for 12 merit scholarships which were awarded to students whose poster presentations were judged the best at the conference. This amount covered a significant part of their travel and registration fees.

The quantum mechanics/molecular mechanics (QM/MM) approach is an essential and well-established tool in computational chemistry that has been widely applied in a myriad of biomolecular problems in the literature. In this publication, we report the integration of the QUantum Interaction Computational Kernel (QUICK) program as an engine to perform electronic structure calculations in QM/MM simulations with AMBER. This integration is available through either a file-based interface (FBI) or an application programming interface (API). Since QUICK is an open-source GPU-accelerated code with multi-GPU parallelization, users can take advantage of “free of charge” GPU-acceleration in their QM/MM simulations. In this work, we discuss implementation details and give usage examples. We also investigate energy conservation in typical QM/MM simulations performed at the microcanonical ensemble. Finally, benchmark results for two representative systems, the N-methylacetamide (NMA) molecule and the photoactive yellow protein (PYP) in bulk water, show the performance of QM/MM simulations with QUICK and AMBER using a varying number of CPU cores and GPUs. Our results highlight the acceleration obtained from a single or multiple GPUs; we observed speedups of up to 38x between a single GPU vs. a single CPU core and of up to 2.6x when comparing four GPUs to a single GPU. Results also reveal speedups of up to 3.5x when the API is used instead of FBI.

Structure and dynamics of the Li+ hydrates: A comparative study of conventional QM/MM and ONIOM-XS MD simulations

Molecular dynamics and alignment studies of silica-filled 4-pentyl-4′-cyanobiphenyl (5CB) liquid crystal

Transesterification is an essential process in bioproduct production, with catalyst choice being critical for reaction efficiency and selectivity. Lipases are effective biocatalysts due to their specificity and mild reaction conditions. This study employed computational chemistry and laboratory experiments to compare the enzymatic transesterification of ariri coconut oil with α-bisabolol and ethanol. Computational analyses using molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) evaluated reaction stability and efficiency. The transesterification reactions carried out in the laboratory were carried out under different conditions using Burkholderia cepacia lipase as a biocatalyst. The products were analyzed by thin-layer chromatography (TLC). Computational results indicated that the activation energy (ΔG‡) for the reaction with α-bisabolol exceeded 20 kcal/mol, while for ethanol, it was 19.2 kcal/mol, suggesting a lower energy barrier for ethanol. Gibbs free energy (ΔG) was over 20 kcal/mol for α-bisabolol and 13 kcal/mol for ethanol, confirming ethanol as more energetically favorable. Laboratory tests showed product formation only in reactions with ethanol, aligning with computational findings. These results demonstrate ethanol’s efficiency for enzymatic transesterification of ariri oil. This paper contributes to bioproduct innovation by fostering sustainable processes, leveraging local natural resources, and integrating advanced biocatalysis and computational chemistry techniques.

Quantum mechanical/molecular mechanics (QM/MM) methods are interesting to model the impact of a complex environment on the spectroscopic properties of a molecule. In this context, a FROm molecular dynamics to second harmonic Generation (FROG) code is a tool to exploit molecular dynamics trajectories to perform QM/MM calculations of molecular optical properties. FROG stands for "FROm molecular dynamics to second harmonic Generation" since it was developed for the calculations of hyperpolarizabilities. These are relevant to model non-linear optical intensities and compare them with those obtained from second harmonic scattering or second harmonic generation experiments. FROG's specificity is that it is designed to study simple molecular liquids, including solvents or mixtures, from the bulk to the surface. For the QM/MM calculations, FROG relies on the Dalton package: its electronic-structure models, response theory, and polarizable embedding schemes. FROG helps with the global workflow needed to deal with numerous QM/MM calculations: it permits the user to separate the system into QM and MM fragments, to write Dalton's inputs, to manage the submission of QM/MM calculations, to check whether Dalton's calculation finished successfully, and finally to perform averages on relevant QM observables. All molecules within the simulation box and several time steps are tackled within the same workflow. The platform is written in Python and installed as a package. Intermediate data such as local electric fields or individual molecular properties are accessible to the users in the form of Python object arrays. The resulting data are easily extracted, analyzed, and visualized using Python scripts that are provided in tutorials.

We investigate the effect of systematically applying molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) to docked poses in an attempt to improve the correspondence between theoretical prediction and experimental observation. The proposed scheme involves running a short time scale MD simulation on a docked ligand pose (and any known structurally important crystal structure waters in the active site), followed by QM/MM minimization. Both of these steps are relatively fast for moderately sized ligands; longer time scale MD involving the protein is not found to improve the results. The final binding energy is given in terms of the QM/MM total energy, a van der Waals correction, and a term to account for desolvation effects. This methodology is first tested with a trypsin inhibitor, for which we establish the importance of running MD before reoptimizing with QM/MM. The method is then applied to cytochrome c peroxidase using a set of binders and decoys. In this example, the proposed methodology affords much better discrimination between binders and decoys than the traditional docking approach used. For both systems presented, application of this protocol results in a significantly better energetic ranking and a smaller root mean squared deviation from known crystallographic ligand poses. This work highlights the importance of including polarization effects through QM/MM and of sampling with MD to refine a set of initial docked poses.

All-aromatic calamitic liquid crystals are an unconventional family of rigid linear mesogens that represents the closest embodiment of the idealised rod-like molecule central to liquid crystal theories. 2,6-biphenyl naphthalene (PPNPP), a prototypical all-aromatic nematogen, has recently been the focus of scientific interest for both fundamental and technological purposes. While it provides a valuable benchmark for classical theories of nematic order, its experimental study presents challenges given the high temperature of the nematic phase. Herein, molecular dynamics (MD) simulations are contrasted with X-ray diffraction (XRD) data to resolve the thermotropic phase behaviour of PPNPP and the main structural features of its liquid crystal order. The observed trend of the molecular conformation with temperature points to an unexpected and significant distortion of the molecular framework in the nematic phase, which demonstrates the substantial non-linearity of the PPNPP molecule. The simulated mesomorphic behaviour and related thermodynamic parameters are in close agreement with the experimental data. The different phases are described in terms of their molecular organisation, pair distribution function, as well as the orientational and positional order parameters. We compare the classical and extended Maier-Saupe nematic theories with the computationally (MD) and experimentally (XRD) determined orientational order parameters. The observed deviation from the theoretical models indicates substantial inadequacies of the classical theories to describe the nematic-isotropic phase transition for this class of compounds. We suggest that modifications of theory should include the effects of short-range positional order, i.e., cybotaxis.

The previously introduced workflow to achieve an energetically and structurally optimized description of frontier bonds in quantum mechanical/molecular mechanics (QM/MM)-type applications was extended into the regime of computational material sciences at the example of a layered carbon model systems. Optimized QM/MM link bond parameters at HSEsol/6-311G(d,p) and self-consistent density functional tight binding (SCC-DFTB) were derived for graphitic systems, enabling detailed investigation of specific structure motifs occurring in graphene-derived structures quantum-chemical calculations. Exemplary molecular dynamics (MD) simulations in the isochoric-isothermic (NVT) ensemble were carried out to study the intercalation of lithium and the properties of the Stone-Thrower-Wales defect. The diffusivity of lithium as well as hydrogen and proton adsorption on a defective graphene surface served as additional example. The results of the QM/MM MD simulations provide detailed insight into the applicability of the employed link-bond strategy when studying intercalation and adsorption properties of graphitic materials.

A review of basic physical phenomena underlying the light-induced molecular reorientation in nematic liquid crystals is presented. A detailed description of the mechanisms of direct optical torque, photoisomerization and photorefractivity and of their effect on the macroscopic order of liquid crystals is reported. The first part of the article deals with the study of reorientation effects in transparent liquid crystalline materials. Here, the effects of photo-induced molecular reorientation are fully interpreted within the framework of classical electrodynamics and standard continuum theory of liquid crystals. We investigate the peculiar properties related to the macroscopic anisotropy and the collective behaviour of liquid crystals that result in extraordinarily large nonlinear optical response. Afterwards, the behaviour of liquid crystals in the presence of light absorption is considered and the related reorientation effects are discussed. We give a review of the wide phenomenology which is met in liquid crystals when doped with absorbing azo-dye molecules. The photoisomerization process that in this case drives the evolution of the dye-liquid crystal mixture consequent to the interaction with the light is discussed in detail. Finally, the relatively new field of photorefractivity in liquid crystals as a source of molecular reorientation is considered. We describe the different mechanisms contributing to the creation of a space-charge field such as conductivity anisotropy, dielectric anisotropy and photocharge production. A theoretical discussion of the fundamental mechanisms regulating the dc-field-assisted optically induced space-charge fields and the optical molecular reorientation in nematic liquid crystal films is also given.

p21ras protein activity, regulated by GTP hydrolysis, constitutes an active field of research for the development of cancer targeted therapies that would concern ∼30% of human tumors to which specific mutations have been associated. Indeed, the catalyzing mechanisms provided by the protein environment during GTP hydrolysis and how they are impaired by specific mutations remain to be fully elucidated. In this article, we present results from molecular mechanics (MM) molecular dynamics (MD) simulations and density functional theory (DFT) calculations carried out for wild-type p21 N-ras and six Gln 61 mutants. In the first part, we present the water distribution within the active site of the wild-type protein according to MM MD. Significant differences are observed when comparing the results to the previous distribution assessed through quantum mechanics/molecular mechanics (QM/MM) MD. Such method-dependent results highlight the importance of accounting for the electrostatic coupling between the protein complex and the solvent molecules in identifying hydration sites. In the second part, we present the results from DFT calculations performed to determine the electronic distribution of the GTP ligand, considering the wild-type active site arrangement according to both classical and hybrid approaches. Only in the QM/MM-based configuration is the ligand electronic density similar to that of a GDP-like state observed experimentally. For this reason, in the last set of calculations carried out for p21 N-ras Gln 61 mutants, only the active site structural conformations obtained through hybrid MD are considered. Through the analysis of the GTP electronic density, we conclude that the wild-type active site arrangement according to QM/MM MD is closer to a catalytically efficient conformation of the protein than the arrangement according to MM MD. Hence, water distribution according to the hybrid approach must correspond to the optimal placement of solvent in the active site. Within all of the studied Gln 61 substituted proteins, p21ras major catalyzing effect, which consists of stabilizing a more GDP-like state, is lost.

Thiols are widely present in biological systems, most notably as the side chain of cysteine amino acids in proteins. Thiols can be deprotonated to form a thiolate which affords a diverse range of enzymatic activity and modes for chemical modification of proteins. Parameters for modeling thiolates using molecular mechanical force fields have not yet been validated, in part due to the lack of structural data on thiolate solvation. Here, the CHARMM36 and Amber models for thiolates in aqueous solutions are assessed using free energy perturbation and hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. The hydration structure of methylthiolate was calculated from 1 ns of QM/MM MD (PBE0-D3/def2-TZVP//TIP3P), which shows that the water-S- distances are approximately 2 Å with a coordination number near 6. The CHARMM thiolate parameters predict a thiolate S radius close to the QM/MM value and predict a hydration Gibbs energy of -329.2 kJ/mol, close to the experimental value of -318 kJ/mol. The cysteine thiolate model in the Amber force field underestimates the thiolate radius by 0.2 Å and overestimates the thiolate hydration energy by 119 kJ/mol because it uses the same Lennard-Jones parameters for thiolates as for thiols. A recent Drude polarizable model for methylthiolate with optimized thiolate parameters also performs well. SAPT2+ [Symmetry Adapted Perturbation Theory (SAPT)] analysis indicates that exchange repulsion is larger for the methylthiolate, consistent with it having a more diffuse electron density distribution in comparison with the parent thiol. These data demonstrate that it is important to define distinct non-bonded parameters for the protonated/deprotonated states of amino acid side chains in molecular mechanical force fields.

A combination of X-ray absorption spectroscopy (XAS) measurements and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) simulations has been applied to elucidate detailed information on the hydration structures of Ca(2+) and Cl(-). The XAS spectra (extended X-ray absorption fine structure, EXAFS, and X-ray absorption near-edge structure, XANES) measured from aqueous CaCl(2) solution were analyzed and compared to those generated from snapshots of QM/MM MD simulations of Ca(2+) and Cl(-) in water. With regard to this scheme, the simulated QM/MM-EXAFS and QM/MM-XANES spectra, which correspond to the local structure and geometrical arrangement of the hydrated Ca(2+) and Cl(-) at molecular level show good agreement with the experimentally observed EXAFS and XANES spectra. From the analyses of the simulated QM/MM-EXAFS spectra, the hydration numbers for Ca(2+) and Cl(-) were found to be 7.1 +/- 0.7 and 5.1 +/- 1.3, respectively, compared to the corresponding values of 6.9 +/- 0.7 and 6.0 +/- 1.7 derived from the measured EXAFS data. In particular for XANES results, it is found that ensemble averages derived from the QM/MM MD simulations can provide reliable QM/MM-XANES spectra, which are strongly related to the shape of the experimental XANES spectra. Since there is no direct way to convert the measured XANES spectrum into details relating to geometrical arrangement of the hydrated ions, it is demonstrated that such a combined technique of XAS experiments and QM/MM MD simulations is well-suited for the structural verification of aqueous ionic solutions.

The synthesis and characterization of two half-sandwich complexes of Ru(II) and Ir(III) with thiabendazole as ancillary ligand and their DNA binding ability were investigated using experimental and computational methods. 1H NMR and acid-base studies have shown that aquo-complexes are the reactive species. Kinetic studies show that both complexes bind covalently to DNA through the metal site and non covalently through the ancillary ligand. Thermal stability studies, viscosity, circular dichroism measurements and quantum chemical calculations have shown that the covalent binding causes breaking of the H-bonding between base pairs, bringing about DNA denaturation and compaction. Additionally, molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations shed light into the binding features of the Ru(II) and Ir(III) complexes and their respective enantiomers toward double-helical DNA, highlighting the important role played by the NˆN ancillary ligand once the complexes are covalently linked to DNA. Moreover, metal quantification in the nucleus of SW480 colon adenocarcinoma cells were carried out by inductively coupled plasma-mass spectrometry (ICP-MS), both complexes are more internalized than cisplatin after 4h of exposition. However, in spite of the dramatic changes in the helicity of the DNA secondary structure induced by these complexes and their nuclear localization, antiproliferative studies have revealed that both, Ru(II) and Ir(III) complexes, cannot be considered cytotoxic. This unexpected behavior can be justified by the fast formation of aquo-complexes, which may react with components of the cell culture medium or the cytoplasm compartment in such a way that they may become deactivated before reaching DNA.

Plasmepsin (PM) II is one of four enzymes in the food vacuole of Plasmodium falciparum. It has become an attractive target for combating malaria through research regarding its importance in the P. falciparum metabolism and life cycle, making it the target of choice for structure-based drug design. This paper reports the results of hybrid quantum mechanics / molecular mechanics (QM/MM) molecular dynamics (MD) simulations employed to study the details of the interactions established between PM II and N-(3-{(2-benzo[1, 3]dioxol-5-yl-ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-yl) propionyl]-amino}-1-benzyl-2-(hydroxyl-propyl)-4-benzyloxy-3,5dimethoxy-benzamide (EH58), a well-known potent inhibitor for this enzyme. Electrostatic binding free energy and energy terms decomposition have been computed for PM II complexed with the EH58 inhibitor. The results reveal that there is a strong interaction between Asp34, Val78, Ser79, Tyr192 and Asp214 residues and the EH58 inhibitor. In addition, we have computed the potential of the mean force (PMF) profile in order to assign the protonation state of the two catalytic aspartates in PM II-EH58 complex. The results indicate that the protonation of Asp214 favors a stable active site structure, which is consistent with our electrostatic binding free energy calculation and with previous published works.