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64ee4a7479853bbd78b21dc7 | 16 | ORDerly-forward is a benchmark created from USPTO data in ORD for retrosynthesis prediction consisting of reactions with up to two products and three reactants, solvents, and agents. A random 80/10/10 train/val/test split was applied to the benchmark. An additional test set called non-USPTO-forward was created by using... |
64ee4a7479853bbd78b21dc7 | 17 | ORDerly-retro is a benchmark created from USPTO data in ORD for retrosynthesis prediction consisting of reactions with one product and up to two reactants. A random 80/10/10 train/val/test split was applied to the benchmark. An additional test set called non-USPTO-retro was created by using all non-USPTO data in ORD (a... |
64ee4a7479853bbd78b21dc7 | 18 | ORDerly-condition is a benchmark dataset created from USPTO data in ORD for reaction condition prediction, and is, to the best of our knowledge, the first reaction condition benchmark. Each reaction in ORDerly-condition contains one product and up to two reactants, two solvents, and three agents. A minimum frequency of... |
64ee4a7479853bbd78b21dc7 | 19 | Experimental evaluation of the ORDerly-forward and ORDerly-retro benchmarks was performed using the Molecular Transformer architecture built by Schwaller et al. . To switch from forward prediction to retrosynthesis prediction no changes to the transformer architecture were necessary, only the data was changed. The ORDe... |
64ee4a7479853bbd78b21dc7 | 20 | On the forward prediction tasks the accuracies achieved are similar (albeit slightly lower) to the accuracies reported by by Schwaller et al. (88-90% top-1 accuracy when trained on the USPTO_MIT dataset), though the accuracies are not directly comparable since different subsets of USPTO were used. As expected the perfo... |
64ee4a7479853bbd78b21dc7 | 21 | The reaction condition prediction model used in this work predicts five categorical variables: two solvents and three agents. These five molecules form a set (order invariant), though the loss function in the model used to predict the molecules considers them sequentially (with order) since this was found to work bette... |
64ee4a7479853bbd78b21dc7 | 22 | Table shows the predictive performance on the test set using four different flavours of the ORDerly-condition benchmark. All models show an improvement over the frequency informed baseline. The performance of the labeling datasets at first appears to be better than those that use our custom logic to extract reaction co... |
64ee4a7479853bbd78b21dc7 | 23 | For the datasets that extract the components from the reaction string, overall top-3 accuracy is less than 25% across solvents and agents. While not directly comparable, our overall accuracy is lower than what Gao et al. achieved with 50.1% top-3 accuracy across catalysts, solvents and agents. However, Gao et al. train... |
64ee4a7479853bbd78b21dc7 | 24 | Finally, the approach to dealing with rare values is investigated. The reaction string datasets would have more than 10,000 unique agents (see Table ) with no frequency based filtering, which would create a sparse OHE. We initially hypothesized that the rare ! "other" strategy would allow for better generalisation, sin... |
64ee4a7479853bbd78b21dc7 | 25 | There are two ways of assigning reaction roles to molecules found in ORD files, either relying on the labeling, or identifying reaction roles by considering the atom mapping of a reaction SMILES string. We found that relying on the labeling in ORD mislabels many spectator molecules as reactants, which explains the diff... |
64ee4a7479853bbd78b21dc7 | 26 | Although order of addition may play a role in wet lab chemistry, reaction prediction tasks are often cast as order invariant, where the goal is to predict a set of molecules. However, both of the architectures used for experimental validation of the ORDerly datasets are not agnostic to the ordering of the targets, sinc... |
64ee4a7479853bbd78b21dc7 | 27 | In this work, we presented ORDerly, an open-source framework for preparing chemical reaction data stored in the Open Reaction Database (ORD) for machine learning applications. ORDerly was used to generate benchmark datasets for forward prediction (ORDerly-forward), retrosynthesis (ORDerly-retro), and condition predicti... |
64ee4a7479853bbd78b21dc7 | 28 | All benchmarks and datasets experimented with in this work, as well as the code used to generate them, are freely available online, and we hope the benchmarks will make reaction prediction tasks more accessible to ML practitioners with limited domain knowledge. ORDerly presents a fully open-source pipeline to go from r... |
66f4241e51558a15ef144cfa | 0 | The fourth mechanism involves instances where small crystals come together and fuse in a specific, orientation-dependent manner to form a larger crystal (Extended Data Movie 4). This process differs from the more common random aggregation leading to polycrystalline structures; here, the particles align according to the... |
66f4241e51558a15ef144cfa | 1 | We therefore employ our previously developed computational model to confirm that these mechanisms emerge naturally from our proposed interaction potential. We perform simulations of 210 nm and 170 nm particles interacting via a pair potential that accounts for the combination of surface charge and polymer brush coating... |
66f4241e51558a15ef144cfa | 2 | A representative example of the formation of CsCl-like crystals can be seen in Extended Data Movie 1. Here, nucleation occurs from within these blobs, often starting from the surface where interfacial fluctuations more easily allow for transient changes in density. For lower interaction strengths, particles can rearran... |
66f4241e51558a15ef144cfa | 3 | To assess the generality of this two-step crystallization process, we conducted crystallization experiments varying the size ratio (β) between positive and negative particles. As shown in Extended Data Figure , we observed no substantial differences in the crystallization mechanism, although the resulting crystal struc... |
66f4241e51558a15ef144cfa | 4 | We hypothesized that the strength and range of particle interactions plays a crucial role in modulating the crystal formation pathways we observed, a phenomenon also noted in various other colloidal and molecular systems. To explore this, we concentrated on designing experiments that allowed us to gradually, and in a c... |
66f4241e51558a15ef144cfa | 5 | Continuous dialysis allows us to create well-defined, spatially and temporally variable interaction potentials between particles, enabling the identification of optimal conditions for crystal growth in a single experiment. By assessing the size and quality of the crystals in various regions of the observation cell at t... |
66f4241e51558a15ef144cfa | 6 | Continuous dialysis allows us to discover and spatially resolve crystal structures with similar nucleation energy barriers, which might be overlooked in experiments using static interaction potentials. For example, in sealed capillaries, binary mixtures with β = 0.81 primarily form CsCl-like crystals that take on macro... |
66f4241e51558a15ef144cfa | 7 | In addition to the Th 3 P 4 crystals, we have discovered a previously unreported crystal structure that, surprisingly, forms in the same sample from the same building blocks and exhibits a distinctive needle-like morphology (Fig. ). As shown in Figure ,b, this crystal features an unusual open structure with empty chann... |
66f4241e51558a15ef144cfa | 8 | By analyzing the distribution of distances between particles, we constructed the crystal's unit cell, which has a 3:4 ratio of large to small particles and a remarkably low volume fraction of 56%. Hereafter, we refer to this new crystal as L 3 S 4 . Unlike CsCl and Th 3 P 4 , L 3 S 4 seems to nucleate only heterogeneou... |
66f4241e51558a15ef144cfa | 9 | While in the middle of our dialysis setup we observe regions where each one of these structures seem to be individually dominant (Figure ), towards the sealed end of the capillary, we observe coexistance of all three of these structures and several others within a single field of view (Fig. and Extended Fig. ). Since t... |
66f4241e51558a15ef144cfa | 10 | So far, we have described how our dialysis setup allowed us to observe formation of numerous large binary single crystals with an array of forms for a system prepared with a fixed ratio of particle size, surface charge, and number ratio. Within our setup, we are also able to observe more complex hierarchical assemblies... |
66f4241e51558a15ef144cfa | 11 | A particularly promising outcome of this work is the potential to control the formation of specific structures or polymorphs by creating charged patterns on the substrate. 9 Low-density (ρ = 1.05 g/cm 3 ) polystyrene (PS) and low-refractive-index (n = 1.39) pentafluoropropyl methacrylate (PFPMA) colloids were synthesiz... |
66f4241e51558a15ef144cfa | 12 | The surface potential of each particle system was measured using a Malvern Zetasizer Nano ZS with DTS1070 folded capillary cells. Measurements were performed on highly dilute samples equilibrated in 10 mM NaCl. Zeta potentials were calculated using the Smoluchowski approximation (Henry's function f (κa) = 1.5), with re... |
66f4241e51558a15ef144cfa | 13 | Oppositely charged PS particles were separately equilibrated with 0.1 wt% Pluronic F108 and 2-5 mM NaCl for 30 minutes. They were then mixed together while vortexing. The resulting mixture was promptly transferred into hydrophobized borosilicate glass capillaries (VitroCom, model 3520), which were then sealed on both e... |
66f4241e51558a15ef144cfa | 14 | CsCl-like crystals (space group P m3m, No. 221) were formed using particle size ratios ranging from 0.8 to 1.0 and a number ratio of 1:1. The Wulff shape of these crystals is a rhombic dodecahedron, bound by {110} planes, reflecting their equilibrium shape as determined by surface energy minimization (Extended Data Fig... |
66f4241e51558a15ef144cfa | 15 | NaCl-like crystals (space group F m3m, No. 225) were formed using 300 nm (+) PS and 130 nm (-) PS particles (β = 0.43) at a 1:1 number ratio. A precise size ratio of approximately √ 2 -1 is required to form NaCl crystals; otherwise, K 4 C 60 is typically observed. The Wulff shape of these crystals is a cube, bound by {... |
66f4241e51558a15ef144cfa | 16 | K 4 C 60 -like crystals (space group I4/mmm, No. 139) were formed using 350 nm (+) PS and 160 nm (-) PS particles (β = 0.46) at a 1:4 number ratio, as well as 200 nm (+) PS and 400 nm (-) PS particles (β = 0.50) at the same number ratio. The larger particles are positioned at the body-centered cubic (bcc) lattice sites... |
66f4241e51558a15ef144cfa | 17 | To perform experiments at variable interaction potentials, mixtures of oppositely charged PS particles with 4.5 mM NaCl and 0.1 wt% F108 were introduced into 50-mm-long glass capillaries (inner dimensions: 2.0 mm × 0.2 mm, VitroCom) and sealed at one end. The capillaries were then immersed in 100 mm diameter Petri dish... |
66f4241e51558a15ef144cfa | 18 | Bright-field images and movies were acquired using a Leica DMI3000 inverted microscope equipped with differential interference contrast optics and high-resolution cameras: a grayscale Jenoptik Gryphax Rigel and a color FLIR Grasshopper3. Crystal nucleation was observed within hours using a 100X oil immersion objective.... |
66f4241e51558a15ef144cfa | 19 | Time-lapse z-stacks of scanning fluorescent images were acquired using a Leica SP8 confocal microscope equipped with a 100X oil objective, recording the crystallization process of positively charged 375 nm and negatively charged 440 nm PFPMA particles in 40% DMSO at 30-minute intervals. The two BODIPY dyes were excited... |
66f4241e51558a15ef144cfa | 20 | Electron Microscopy imaging was performed on fixed samples. Crystals formed in sealed capillaries were fixed by immersing the capillaries in a deionized water bath and carefully removing the sealant (wax or epoxy). The capillaries were then left undisturbed in the deionized water to allow the salt to diffuse into the w... |
66f4241e51558a15ef144cfa | 21 | where J j is the flux of salt, D is the diffusion coefficient of salt (1.61 × 10 -9 m 2 /s), and c j is the concentration of component j. The initial NaCl concentration throughout the capillary was 4.5 mM, with boundary conditions applied such that the interface at one end was fixed at 0 mM, and there was no flux acros... |
66f4241e51558a15ef144cfa | 22 | where ϵ is the dielectric constant taken to be 80.1, ϵ 0 is the vacuum permittivity, R is the ideal gas constant, F is Faraday's constant, T is the temperature and C is the salt concentration in units of mol/L. The attractive interaction strength is then found by finding the minimum of the attractive potential between ... |
66f4241e51558a15ef144cfa | 23 | To model the assembly of charged colloids, we performed Langevin dynamics simulations of binary mixtures of colloidal particles using the HOOMD-Blue software, 37 as previously implemented. † A total 6750 number of charged particles were placed in the simulation boxes in a simple cubic arrangement in a 1:1 ratio at vary... |
66f4241e51558a15ef144cfa | 24 | Here, ϵ is the solvent permittivity which was set to 80, ψ i and ψ j are the surface potentials for the two particles which unless otherwise indicated were set to +50 mV and -50 mV for positive and negative particles, respectively, and λ D is the Debye length. h ij is the distance between the surfaces of the particles.... |
66f4241e51558a15ef144cfa | 25 | The repulsion radius, a R ij , present in the pre-factor is given by a R ij = (r i + r j )/2. L, the polymer brush length, is set to 10 nm for all simulations. 41 σ is the polymer brush density which is equal to 0.09 nm -2 . The simulations were performed at six different values of ϕ p , and for each, unless otherwise ... |
66f4241e51558a15ef144cfa | 26 | To study the effect of a charged substrate on the crystallization, we included a negatively charged wall at position Z min in the simulation box. The charged wall is formed of a hexagonal arrangement of spherical particles of radius 30 nm. The interaction between the charged wall and a colloid particle was modeled usin... |
66f4241e51558a15ef144cfa | 27 | In addition to simulating the size ratio of 0.81, we performed simulations with size ratio of 0.45 (r P = 176.5 nm and r N = 80 nm) and number ratio (positive to negative particles) of 1:2 to produce K 4 C 60 crystals (see Extended Fig. ). Simulations using experimentally realistic surface potentials of positive and ne... |
61d837ab5015eb393fb14e74 | 0 | Since the introduction of the QM/MM approach by Warshel and Levitt in 1976 it has evolved to a broadly used tool in computational chemistry. Dividing a large biomolecular system into two subsystems, one smaller subsystem treated quantum-mechanically (QM) and one larger subsystem treated with molecular mechanics (MM), a... |
61d837ab5015eb393fb14e74 | 1 | The convergence of QM/MM results with the choice and particularly the size of the QM region has been investigated in several studies, which underline that it generally has a large effect on the quality of the final results, and that often rather large QM regions are required for reaching converged results. To alleviate... |
61d837ab5015eb393fb14e74 | 2 | Consequently, there is a need for rigorous uncertainty quantification for QM/MM calculations, i.e., to systematically assess the sensitivity of the QM/MM energy with respect to these technical choices and empirical parameters and to ultimately provide rigorous error bounds on the results of QM/MM calculations (compared... |
61d837ab5015eb393fb14e74 | 3 | The ability to quantify the sensitivity of QM/MM calculations with respect to parameters of the MM environment provides a natural starting point for guiding the systematic choice of the QM region. With increasing size of the QM region and approaching a full QM calculation, one can expect this sensitivity to decrease. T... |
61d837ab5015eb393fb14e74 | 4 | 2.1 QM/MM energy partitioning QM/MM is based on the partitioning of the full target system into a QM region (A) including the interesting part of the system, such as the active center of an enzyme, and an MM region (B) containing all other atoms, i.e., the active center's environment. The total energy can be expressed ... |
61d837ab5015eb393fb14e74 | 5 | The energy of the QM region, E QM (A), is obtained from a quantum-chemical calculation of the corresponding subsystem A. To allow for covalent bonds to cross the boundary between the QM and MM regions, the QM subsystem is usually saturated using capping atoms. The energy of the MM region, E MM (B), is calculated using ... |
61d837ab5015eb393fb14e74 | 6 | In the electrostatic embedding scheme, which is commonly used when applying QM/MM to enzymatic reactions, the electron density of subsystem A is polarized by the MM point charges of subsystem B. The MM point charges are included in the QM Hamiltonian 4 to compute the interaction between the electron density ρ A (r) of ... |
61d837ab5015eb393fb14e74 | 7 | The reaction energy calculated within a QM/MM model is subject to numerous sources of uncertainty (see Introduction). One important element of uncertainty quantification is the analysis of the sensitivity of the simulation results with respect to its input parameters. Here, we consider the QM/MM reaction energy ∆E reac... |
61d837ab5015eb393fb14e74 | 8 | We consider the MM point charges q MM as one of the most important sources of uncertainty and want to systematically analyze the effect of variations in the MM point charges on our QoI, i.e., the reaction energy ∆E reaction QM/MM (q MM ). To this end, we follow our earlier work on the sensitivity of calculated spectra ... |
61d837ab5015eb393fb14e74 | 9 | where q MM is a vector of size N B containing all MM point charges, q 0 MM is the vector of the undistorted MM point charges as provided by the employed force field, and ∆q MM is a collective variation of these point charges, which depends on a parameter ∆q that controls the size of the variation. We chose the collecti... |
61d837ab5015eb393fb14e74 | 10 | where N aa,i is the number of atoms in the i-th amino acid. The first will provide an estimate of the overall sensitivity of the QM/MM reaction energy to variations of the MM point charges, while the second will allow us to assess the effect of the individual single amino acids. |
61d837ab5015eb393fb14e74 | 11 | Molecular dynamics calculations were performed using GROMACS 2019.3 with the AMBER99SB-ILDN force field. The already equilibrated initial structure provided by Ku-lik et al. in the Supporting Information of Ref. 15 was solvated in TIP3P water molecules in a cubic simulation box with 1 nm distance between the borders an... |
61d837ab5015eb393fb14e74 | 12 | All QM/MM calculations were performed using the Amsterdam Modeling Suite (AMS Version 2020.203). The Amsterdam Density Functional (ADF) engine was used for the QM part applying density functional theory (DFT) with the PBE exchange-correlation functional employing a DZ and a TZP Slater-type orbital basis set 49 for all ... |
61d837ab5015eb393fb14e74 | 13 | were achieved using Python. Plots were generated with Matplotlib 58,59 and structures were visualized using Vmd. A data set containing PDB files of the reactant and product starting structures, a modified AMBER95 force field file, AMS fragment files for the ligands and ions, and the AMS input files for all geometry opt... |
61d837ab5015eb393fb14e74 | 14 | To test the overall QM region size convergence we first evaluated the distances between SAM methyl and the catecholate oxygen atom in the reactant structures (see Supporting Information, Fig. ). The SAM to catechol distance in the initial MM-equilibrated structure before QM/MM optimization is 3.11 Å which is similar to... |
61d837ab5015eb393fb14e74 | 15 | Overall, it can be stated that small QM regions are not sufficient for reproducing the ligand charges found for large QM regions because important residues coordinating the ligands might be missing. When using a distance-based construction of the QM region, rather larger QM regions need to be reached before all relevan... |
61d837ab5015eb393fb14e74 | 16 | For small QM regions, the reaction energy shows large oscillations, while starting from QM Overall, our results confirm the slow convergence of the reaction energy with increasing size of the QM region found in earlier studies and emphasize the need for systematic protocols for the construction and selection of the QM ... |
61d837ab5015eb393fb14e74 | 17 | found that in COMT, the activation barrier shows a much smaller sensitivity with respect to the choice of the QM region than the reaction energy. Therefore, we will not consider activation barriers and focus on the reaction energies in the present work. In addition to the VDD charges obtained with the undistorted MM ch... |
61d837ab5015eb393fb14e74 | 18 | Significant deviations from the unvaried curve are visible for ∆q = ±0.005. Overall, the variations do not affect the charge convergence behavior, but lead to different ligand-dependent observations concerning the sensitivity. For CAT and Mg 2+ , the VDD charge sensitivity decreases with increasing QM region size (with... |
61d837ab5015eb393fb14e74 | 19 | For SAM, in contrast to CAT and Mg 2+ , the VDD charge sensitivity is initially increasing until a QM region size of about 300 atoms is reached (region 4), before the sensitivity starts to slightly decrease when further enlarging the QM region. This different behavior arises because SAM is a much larger molecule than C... |
61d837ab5015eb393fb14e74 | 20 | The plot of the QM/MM reaction energies for the different QM regions in Fig. also includes the reaction energies obtained for collective point-charge variations ∆q tot MM , whereas Fig. shows the corresponding sensitivities δ∆E reaction QM/MM . The point charge variation leads to significant changes in the reaction ene... |
61d837ab5015eb393fb14e74 | 21 | Overall, these first point charge variation tests show that small changes in the MM point charges have an impact on the QM region. While VDD charges and the reaction energy slowly converge for larger QM regions, the corresponding sensitivities to global point-charge variations decrease, whereas outliers are accompanied... |
61d837ab5015eb393fb14e74 | 22 | Motivated by the results of a global point charge variation analysis presented in the previous section, we set out to develop a protocol of the systematic construction of the QM region that aims at minimizing the sensitivity of the QM/MM reaction energy. To this end, we consider the sensitivity of the QM/MM reaction en... |
61d837ab5015eb393fb14e74 | 23 | As starting point, we consider the minimal QM/MM model with QM region 1, i.e., for our COMT test case only the ligands and the catalytically active magnesium ion are included in the QM region. For single-point energy calculations of the geometry-optimized reactant and product structures, we calculate the sensitivity of... |
61d837ab5015eb393fb14e74 | 24 | To reduce the computational effort for the evaluations of this sensitivity for each amino acid, we assessed several possible simplifications compared to the global PCVA in the previous section. The different levels of simplification are referred to as PCVA-A to PCVA-E, and the sensitivities obtained in these different ... |
61d837ab5015eb393fb14e74 | 25 | While this does change the values of the sensitivities, it leads to overall similar trends (cf. Fig. ). Using the product or reactant energy sensitivities could also be advantageous for avoiding error cancelation that might be present when considering the sensitivity of the reaction energy only. Consequently, we choose... |
61d837ab5015eb393fb14e74 | 26 | Naively, it could be expected that residues closer to the active site show higher sensitivities to point charge variations than distant ones. However, there are also several high-sensitivity amino acids at medium distances to the active site and low-sensitivity residues very close to the substrates. This observation co... |
61d837ab5015eb393fb14e74 | 27 | The resulting indicator is plotted in Fig. . A comparison of the indicators for the schemes PCVA-A to PCVA-D is shown in the Supporting Information (Fig. ), and an additional Table lists the 16 amino acid residues with the highest QM region indicators for the schemes PCVA-A to PCVA-E (see also Section 7). When using th... |
61d837ab5015eb393fb14e74 | 28 | Ideally, by using PCVA for a systematic construction of QM regions, the convergence towards the results obtained with very large QM regions should be accelerated compared to an exclusively distance-based construction of the QM region. To this end, we construct QM regions consisting of just as many residues as in the di... |
61d837ab5015eb393fb14e74 | 29 | and label these regions as 2', 3' etc. (e.g., QM regions 3 and 3' both contain seven amino acid residues). Fig. and Tab. S4 in the Supporting Information show which residues are included for each QM region. Again, geometry optimizations of the reactant and product structures were performed for each of these QM regions. |
61d837ab5015eb393fb14e74 | 30 | Fig. shows the convergence of the VDD charges and the QM/MM reaction energy as well as the corresponding sensitivities to global point charge variations (cf. Fig. for the same plot PCVA-constructed QM regions deliver overall lower sensitivities regarding VDD ligand charges (see Fig. ), which marks an expected behavior ... |
61d837ab5015eb393fb14e74 | 31 | The reaction energy (see Fig. ) decreases for the smallest QM regions, starts to stabilize for QM regions 4', and oscillates around our best estimate of about -11 kcal/mol for larger QM regions. However, these oscillations are smaller than for the distance-based construction of the QM regions. Note that compared to Fig... |
61d837ab5015eb393fb14e74 | 32 | In contrast to the distance-based case, a slightly increasing trend is observed for the reaction energy sensitivity (Fig. ). For QM region 8', at which the reaction energy is further from our best estimate, the sensitivity also shows a marked increase. Except for the smallest QM regions, the global PCVA sensitivity can... |
61d837ab5015eb393fb14e74 | 33 | An extreme case with a very low PCVA rank (178) compared to CSA (10) and FSA (10-11) is SER71. This residue is located very close to the active site and thus potentially important for ligand binding, but it shows a very low electrostatic effect on the substrates and is thus not detected by PCVA. Another case is SER118,... |
61d837ab5015eb393fb14e74 | 34 | PCVA also detects residues that are much lower ranked in CSA and FSA. PHE138 and LEU139 are both part of the ligand binding site and obviously have a high electrostatic impact on the substrates. Consequently, PCVA ranks them very high at 12 and 13, respectively, in contrast to FSA (156-163) while CSA also assigns quite... |
61d837ab5015eb393fb14e74 | 35 | In Fig. , we compare the VDD charges of SAM, CAT, and the catalytically-active Mg 2+ cation as well as the QM/MM reaction energy obtained for the atom-economical QM regions constructed using CSA, FSA, and PCVA to those obtained for PCVA-constructed QM regions of increasing size discussed in Section 6. Note that the siz... |
61d837ab5015eb393fb14e74 | 36 | Regarding VDD charges (see Fig. ), PCVA performs as well as CSA and FSA. The change in the Mg 2+ charge to about 0.3 with the distance-based region 8 (34 residues) and larger is achieved already in the QM regions containing 16 residues. For SAM, all three atom-economical QM regions also provide the converged charge. In... |
61d837ab5015eb393fb14e74 | 37 | As a first step towards systematically quantifying the uncertainties of QM/MM calculations, we have presented a point charge variation analysis for assessing the sensitivity of QM/MM reaction energies to changes of the MM point charges. To this end, we considered the derivative of the QM/MM reaction energy with respect... |
61d837ab5015eb393fb14e74 | 38 | This derivative can be calculated numerically by performing QM/MM calculations with varied MM point charges, and different efficient approximations can be employed. Generally, the most simple approximation (PCVA-E), in which a forward finite difference is used and only the reactant structure is considered, turns out to... |
61d837ab5015eb393fb14e74 | 39 | A global PCVA, in which all protein point charges are varied simultaneously, can be used as a simple indicator of the accuracy of the resulting QM/MM reaction energy as well as other properties of the active site, such as ligand charges. For the considered test cases we found that when comparing different QM regions, t... |
61d837ab5015eb393fb14e74 | 40 | Nevertheless, our results demonstrate that the analysis of the sensitivity with respect to the MM point charges is a good starting point for the investigation of uncertainties in QM/MM calculations. We are planning to extent this work in the future by considering not only selected distortions of the MM point charges, b... |
61d837ab5015eb393fb14e74 | 41 | In addition to a global PCVA, we have considered a single amino acid PCVA, in which the MM charges of each amino acid residue are varied. This makes it possible to assess the contribution of each amino acid to the uncertainty in the QM/MM reaction energy, and can be used to guide the systematic construction of the QM r... |
61d837ab5015eb393fb14e74 | 42 | For the considered test case, our scheme leads to a faster and more reliable convergence with the size of the QM region compared to distance-based QM region construction. Comparing to atom-economical QM regions of the same size provided by the other common approaches, in particular CSA and FSA, our PCVA-based approach ... |
61d837ab5015eb393fb14e74 | 43 | The huge advantage of PCVA is its much lower computational cost compared to the CSA or FSA approach (see Supporting Information, Tab. S5). Our PCVA-based approach requires only a geometry optimization of the target system with a minimal QM region including substrates, which is followed by single-point calculations for ... |
61d837ab5015eb393fb14e74 | 44 | The PCVA-based construction of the QM region is limited to the electrostatic effect of the amino acids and thereby lacking other properties which may also play an important role in QM region determination. Therefore, it is possible that crucial residues (e.g. catalytically important) may be absent under the detected re... |
6731b093f9980725cfce7488 | 0 | of mechanochemical reactions, especially for those initiated by tensile force. It is known that stereochemistry plays an important role for determining the activation force F act (i.e., cis-isomers are more reactive than trans-isomers), however, the presence of a highly-strained cyclopropane ring was thought to contrib... |
6731b093f9980725cfce7488 | 1 | A node means the dihedral is lower than 90°, and an ideal node should have a dihedral close to 0°. We found the force transduction is inhibited and meets resistance at "node", causing a severe distortion of the structure and increasing of energy, therefore making a large stress at the node, which finally leads to a bon... |
6731b093f9980725cfce7488 | 2 | A ring or even bulky groups can result in such a rigid σ bond. No significant distortion of bond angles and bond length is observed. An ideal node can have the dihedral angle close to 0°. To generate such a "node", a rigid σ bond that cannot rotate freely, is required. |
6731b093f9980725cfce7488 | 3 | Following this, camphanediol and pinanediol, which are natural products either used in the cosmetics industry or the auxiliary ligand for the synthesis of chiral boron compounds, were selected as candidate mechanophores. Both have a "node", as the bridged ring helps to fix the conformation of O-C-C-O dihedral angle. We... |
6731b093f9980725cfce7488 | 4 | Therefore, camphanediol, to the best of our knowledge, which was never considered reactive under force, is indeed a mechanophore. Further inspection on the force-coupled transition state revealed that its O-C-C-O dihedral angle is only 10.55°, while it is 35.35° for pinanediol, 79.61° for ciscyclohexanediol and 165.92°... |
6731b093f9980725cfce7488 | 5 | Due to the force effect, the generated three-membered ring does not have a "node", and our EX-AFIR calculations suggests that the ring-opening of this three-membered ring requires a much higher activation force of 2700 pN (Figure ). Reaction path explorations regarding the degradation of pinanediol under tensile force ... |
6731b093f9980725cfce7488 | 6 | To confirm the mechano-reactivity of camphanediol and demonstrate its application for selfstrengthening materials, we covalently incorporated these molecules into a promising polymer-double network (DN) hydrogels and investigated their capacity to generate more mechanoradicals and strengthen the materials. We modified ... |
6731b093f9980725cfce7488 | 7 | long-lived radicals (though the later requires a high F act ). In contrast, pinanediol, despite also having a similar low Fact, cannot generate long-lived radicals suitable for application because its intermediate (Pin_Int1) is short-lived and undergo rapid scissile cleavage into the two alkenes (Pin_TS3CC, see Scheme ... |
6731b093f9980725cfce7488 | 8 | More importantly, owing to our selection guideline which does not require strained rings or weak covalent bonds, such a camphanediol-containing DN gel shows a satisfactory thermal and UV stability, and only evolves rapidly when the force stimuli are applied. This theory-driven selection procedure would be promising for... |
648741004f8b1884b731451d | 0 | The increased concentration of CO 2 in the atmosphere is the single most important anthropogenic cause of global warming. Decreasing the release of CO 2 into the atmosphere requires efficient CO 2 capture and separation technologies. Decades of research have been devoted to improving existing gas separation technologie... |
648741004f8b1884b731451d | 1 | Designing polymers with targeted structural and functional properties is challenging due to the practically infinite polymer chemistry design space. Trial-and-error or intuition-based strategies are not efficient, and they are likely to miss optimal solutions due to the complexity of chemical composition and morphology... |
648741004f8b1884b731451d | 2 | Tao et al. used ML models to predict the glass transition temperature of a polymer based on its structural formulation . Later, these authors also did a benchmarking study to compare the predictive power of numerous ML models and showed the importance of structure and feature representations . Xu et al. used ML models ... |
648741004f8b1884b731451d | 3 | Wang et al. used ML models to screen polymers for pervaporation separation and developed a data-driven approach to predict the fractional free volume of polymers . There are also excellent review articles published in the last couple of years that summarize the recent developments in ML studies of polymer properties . |
648741004f8b1884b731451d | 4 | The success of applying ML models to design new polymer membranes for gas separation has been comparatively lacking, largely owing to limitations in data availability. al. used experimental gas permeability data to develop a ML model to predict gas separation in polymer membranes . They have successfully identified sev... |
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