Correction: Cao et al. Fluorinated PEG-PEI Coated Magnetic Nanoparticles for siRNA Delivery and CXCR4 Knockdown. Nanomaterials 2022, 12, 1692.

In the original publication [...].

Highly efficient implementation of analytic nonadiabatic derivative couplings within the pseudospectral method.

A pseudospectral implementation of nonadiabatic derivative couplings in the Tamm-Dancoff approximation is reported, and the accuracy and efficiency of the pseudospectral nonadiabatic derivative couplings are studied. Our results demonstrate that the pseudospectral method provides mean absolute errors of 0.2%-1.9%, while providing a significant speedup. Benchmark calculations on fullerenes (Cn, n up to 100) using B3LYP achieved 10- to 15-fold, 8- to 17-fold, and 43- to 75-fold speedups for 6-31G**, 6-31++G**, and cc-pVTZ basis sets, respectively, when compared to the conventional spectral method.

Comparative genomic analysis provides insight into the phylogeny and potential mechanisms of adaptive evolution of Sphingobacterium sp. CZ-2.

Sphingobacterium is a class of Gram-negative, non-fermentative bacilli that have received widespread attention due to their broad ecological distribution and oil degradation ability, but are rarely involved in infections. In this manuscript, a novel Sphingobacterium strain isolated from wildfire-infected tobacco leaves was named Sphingobacterium sp. CZ-2. NGS and TGS sequencing results showed a whole genome of 3.92 Mb with 40.68 mol% GC content and containing 3,462 protein-coding genes, 9 rRNA-coding genes and 50 tRNA-coding genes. Phylogenetic analysis, ANI and dDDH calculations all supported that Sphingobacterium sp. CZ-2 represented a novel species of the genus Sphingobacterium. Analysis of the specific genes of Sphingobacterium sp. CZ-2 by comparative genomics revealed that metal transport proteins encoded by the troD and cusA genes could maintain the balance of heavy metal ion concentrations in the internal environment of bacteria and avoid heavy metal toxicity while meeting the needs of growth and reproduction, and transport proteins encoded by the malG gene could keep nutrients required for the survival of bacteria. Synteny and genome evolutionary analyses of Sphingobacterium strains implicated that the gene family contraction as a major process in genome evolution, with insertional sequences leading to mutations, deletions and reversals of genes that help bacteria to withstand complex environmental changes. Complete genome sequencing and systematic comparative genomic analysis will contribute new insights into the adaptive evolution of this novel species and the genus Sphingobacterium.

Fluorinated PEG-PEI Coated Magnetic Nanoparticles for siRNA Delivery and CXCR4 Knockdown.

CXC chemokine receptor 4 (CXCR4) is a promising therapeutic target. Previous studies have shown that intracellular delivery of siRNA to knockdown CXCR4 expression in cancer cells is an effective therapeutic strategy. To prepare efficient magnetic nucleic acid carriers, it is now necessary to improve the endocytosis efficiency of PEGylated magnetic nanoparticles. In our work, Heptafluorobutyryl-polyethylene glycol-polyethyleneimine (FPP) was first prepared and then used to coat magnetic nanoparticles (MNPs) to obtain magnetic nanocarriers FPP@MNPs. The materials were characterized by 19 F-Nuclear Magnetic Resonance (NMR), transmission electron microscope (TEM), energy dispersive spectroscopy (EDS), and dynamic light scattering (DLS). The biosecurity of FPP@MNPs was confirmed by cell viability and apoptosis experiments. Cellular uptake of FPP@MNPs and siRNA transfection enhanced by external magnetic fields were detected by fluorescence microscopy, confocal laser microscopy, and flow cytometry. The results show that the cellular uptake efficiency of FPP@MNPs was significantly improved, and transfection efficiency reached more than 90%. The knockdown of CXCR4 on the 4 T1 cell membrane was confirmed by real-time polymerase chain reaction (RT-PCR) and flow cytometry. In conclusion, the fluorinated cationic polymer-coated magnetic nanoparticles FPP@MNPs can be loaded with siRNA to reduce CXCR4 expression as well as be expected to be efficient universal siRNA carriers.

iPReditor-CMG: Improving a predictive RNA editor for crop mitochondrial genomes using genomic sequence features and an optimal support vector machine.

In crops, RNA editing is one of the most important post-transcriptional processes in which specific cytidines (C) in virtually all mitochondrial protein-coding genes are converted to uridines (U). Despite extensive recent research in RNA editing, exploring all of the C-to-U editing events efficiently on the genomic scale remains challengeable. Developing accurate prediction methods for the detection of RNA editing sites would dramatically reduce experimental determination. Therefore, we propose a novel method, iPReditor-CMG (improved predictive RNA editor for crop mitochondrial genomes), to predict crop mitochondrial editing sites using genome sequence and an optimised support vector machine (SVM). We first selected three mitochondrial genomes with known RNA editing sites from Arabidopsis thaliana, Brassica napus and Oryza sativa, released by NCBI, as the training and test sets. The genes and their transcripts from self-sequenced tobacco mitochondrial ATPase were selected as the validation set. The iPReditor-CMG first coded the genome sequences as numerical vectors and then performed an efficient feature selection on the high-dimensional feature space, where the SVM was employed in feature selection and following modelling. The average independent prediction accuracy of intraspecific editing sites across three species was 0.85, and up to 0.91 in A. thaliana, which outperformed the reference models. For the interspecific independent prediction, the prediction accuracy between dicotyledons was 0.78 and the accuracy between dicotyledons and monocotyledons was 0.56, which implies that there might be similarity in the C-to-U editing mechanism in close relatives. Finally, the best model was identified with an independent test accuracy of 0.91 and an AUC of 0.88, which suggested that five unreported feature sequences, i.e. TGACA, ACAAC, GTAGA, CCGTT and TAACA, are closely associated with the editing phenomenon. Multiple tests supported that the iPReditor-CMG could be effectively applied to predict editing sites in crop mitochondria, which may further contribute to understanding the mechanisms of site editing and post-transcriptional events in crop mitochondria.

Pseudospectral implementations of long-range corrected density functional theory.

We have implemented pseudospectral density-functional theory (DFT) with long-range corrected DFT functionals (PS-LRC) in quantum mechanics package Jaguar, and applied it in the calculations of geometry optimizations, dimmer interaction energies, polarizabilities and first-order hyperpolarizabilities, harmonic vibrational frequencies, S1 and T1 excitation energies, singlet-triplet gaps, charge transfer numbers, oscillator strengths, reaction barrier heights, electron-transfer couplings, and charge-transfer excitation energies. From our accuracy benchmark analysis, PS grids, PS dealiasing functions, PS atomic corrections, PS multigrid strategy, PS length scales, and PS cutoff scheme perform well in PS DFT with LRC density functionals with very small and ignorable deviations when compared to the conventional spectral (CS) method. The timing benchmark study of S1 excitation energy calculations of fullerenes (Cn , n up to 540) demonstrates that PS-LRC achieves 1.4-8.4-fold speedups in SCF, 22-32-fold speedups in Tamm-Dancoff approximation, and 6-15-fold speedups in total wall clock time with an average error 0.004 eV of excitation energies compared to the CS method.

Highly efficient implementation of the analytical gradients of pseudospectral time-dependent density functional theory.

The accuracy and efficiency of time-dependent density functional theory (TDDFT) excited state gradient calculations using the pseudospectral method are presented. TDDFT excited state geometry optimizations of the G2 test set molecules, the organic fluorophores with large Stokes shifts, and the Pt-complexes show that the pseudospectral method gives average errors of 0.01-0.1 kcal/mol for the TDDFT excited state energy, 0.02-0.06 pm for the bond length, and 0.02-0.12° for the bond angle when compared to the results from conventional TDDFT. TDDFT gradient calculations of fullerenes (Cn, n up to 540) with the B3LYP functional and 6-31G** basis set show that the pseudospectral method provides 8- to 14-fold speedups in the total wall clock time over the conventional methods. The pseudospectral TDDFT gradient calculations with a diffuse basis set give higher speedups than the calculations for the same basis set without diffuse functions included.

Preparation, characterization, and pharmacodynamic study on deep second degree burns of total flavonoids composite phospholipids liposome gel of Oxytropis falcata Bunge.

Wound healing is the treatment problem after deep second degree (II°) burns. The p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-κB/inhibitory factor-κB (NF-κB/IκB) signal pathways play significant role in angiogenesis and wound repair after burns.This study aimed to investigate the preparation, characterization and pharmacodynamics of the total flavonoids composite phospholipids liposome of Oxytropis falcata Bunge (TFOFB-CPL) on deep II° burns to research its biological activity and underlying mechanism. The TFOFB-CPL was prepared by thin-film dispersion method and the preparation process was optimized via central composite design. The TFOFB-CPL was then characterized by using particle size, polydispersity indexes (PDIs), zeta potential, encapsulation efficiency (EE) and morphology. Moerover, in vitro transdermal test and in vivo pharmacodynamic study included wound healing rate, hematoxylin-eosin (HE) staining, masson staning, western blotting and RT-PCR. The results showed that the therapeutic effects of TFOFB-CPL gel on deep II° burns, especially during wound healing were significant. TFOFB-CPL gel has a sustained-release effect during the treatment of deep II° burns with forming drug depot in the dermis layer. The wound healing rate of TFOFB-CPL gel group was near positive group and better than the other groups. TFOFB-CPL gel could promote the growth of epidermis, skin appendages, fibrovascular and collagen fibers, and had obvious anti-inflammatory effects. Moreover, TFOFB-CPL gel inhibited the activation of p38MAPK and the degradation of IκBα, and promoted the neonatal wounds during the early stage. Therefore, TFOFB-CPL gel could be considered as a novel preparation for treating deep II° burns.

Highly efficient implementation of pseudospectral time-dependent density-functional theory for the calculation of excitation energies of large molecules.

We have developed and implemented pseudospectral time-dependent density-functional theory (TDDFT) in the quantum mechanics package Jaguar to calculate restricted singlet and restricted triplet, as well as unrestricted excitation energies with either full linear response (FLR) or the Tamm-Dancoff approximation (TDA) with the pseudospectral length scales, pseudospectral atomic corrections, and pseudospectral multigrid strategy included in the implementations to improve the chemical accuracy and to speed the pseudospectral calculations. The calculations based on pseudospectral time-dependent density-functional theory with full linear response (PS-FLR-TDDFT) and within the Tamm-Dancoff approximation (PS-TDA-TDDFT) for G2 set molecules using B3LYP/6-31G*(*) show mean and maximum absolute deviations of 0.0015 eV and 0.0081 eV, 0.0007 eV and 0.0064 eV, 0.0004 eV and 0.0022 eV for restricted singlet excitation energies, restricted triplet excitation energies, and unrestricted excitation energies, respectively; compared with the results calculated from the conventional spectral method. The application of PS-FLR-TDDFT to OLED molecules and organic dyes, as well as the comparisons for results calculated from PS-FLR-TDDFT and best estimations demonstrate that the accuracy of both PS-FLR-TDDFT and PS-TDA-TDDFT. Calculations for a set of medium-sized molecules, including Cn fullerenes and nanotubes, using the B3LYP functional and 6-31G(**) basis set show PS-TDA-TDDFT provides 19- to 34-fold speedups for Cn fullerenes with 450-1470 basis functions, 11- to 32-fold speedups for nanotubes with 660-3180 basis functions, and 9- to 16-fold speedups for organic molecules with 540-1340 basis functions compared to fully analytic calculations without sacrificing chemical accuracy. The calculations on a set of larger molecules, including the antibiotic drug Ramoplanin, the 46-residue crambin protein, fullerenes up to C540 and nanotubes up to 14×(6,6), using the B3LYP functional and 6-31G(**) basis set with up to 8100 basis functions show that PS-FLR-TDDFT CPU time scales as N(2.05) with the number of basis functions. © 2016 Wiley Periodicals, Inc.

The VSGB 2.0 model: a next generation energy model for high resolution protein structure modeling.

A novel energy model (VSGB 2.0) for high resolution protein structure modeling is described, which features an optimized implicit solvent model as well as physics-based corrections for hydrogen bonding, π-π interactions, self-contact interactions, and hydrophobic interactions. Parameters of the VSGB 2.0 model were fit to a crystallographic database of 2239 single side chain and 100 11-13 residue loop predictions. Combined with an advanced method of sampling and a robust algorithm for protonation state assignment, the VSGB 2.0 model was validated by predicting 115 super long loops up to 20 residues. Despite the dramatically increasing difficulty in reconstructing longer loops, a high accuracy was achieved: all of the lowest energy conformations have global backbone RMSDs better than 2.0 Å from the native conformations. Average global backbone RMSDs of the predictions are 0.51, 0.63, 0.70, 0.62, 0.80, 1.41, and 1.59 Å for 14, 15, 16, 17, 18, 19, and 20 residue loop predictions, respectively. When these results are corrected for possible statistical bias as explained in the text, the average global backbone RMSDs are 0.61, 0.71, 0.86, 0.62, 1.06, 1.67, and 1.59 Å. Given the precision and robustness of the calculations, we believe that the VSGB 2.0 model is suitable to tackle "real" problems, such as biological function modeling and structure-based drug discovery.

A localized orbital analysis of the thermochemical errors in hybrid density functional theory: achieving chemical accuracy via a simple empirical correction scheme.

This paper describes an empirical localized orbital correction model which improves the accuracy of density functional theory (DFT) methods for the prediction of thermochemical properties for molecules of first and second row elements. The B3LYP localized orbital correction version of the model improves B3LYP DFT atomization energy calculations on the G3 data set of 222 molecules from a mean absolute deviation (MAD) from experiment of 4.8 to 0.8 kcal/mol. The almost complete elimination of large outliers and the substantial reduction in MAD yield overall results comparable to the G3 wave-function-based method; furthermore, the new model has zero additional computational cost beyond standard DFT calculations. The following four classes of correction parameters are applied to a molecule based on standard valence bond assignments: corrections to atoms, corrections to individual bonds, corrections for neighboring bonds of a given bond, and radical environmental corrections. Although the model is heuristic and is based on a 22 parameter multiple linear regression to experimental errors, each of the parameters is justified on physical grounds, and each provides insight into the fundamental limitations of DFT, most importantly the failure of current DFT methods to accurately account for nondynamical electron correlation.

Integrated Modeling Program, Applied Chemical Theory (IMPACT).

We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high-throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function.

Nuclear-magnetic-resonance shielding constants calculated by pseudospectral methods.

We have developed an algorithm based upon pseudospectral (PS) ab initio electronic structure methods for evaluating nuclear magnetic shielding constants using gauge-including atomic orbitals (GIAOs) in the spin-restricted and spin-unrestricted formalisms of Hartree-Fock (HF) theory and density-functional theory (DFT). The nuclear magnetic shielding constants for both 1H and 13C calculated using PS methodology for 21 small molecules have absolute mean errors of less than 0.3 ppm in comparison with analytic integral results. CPU timing comparisons between PS methods and conventional methods carried out for seven large molecules ranging from 510 to 1285 basis functions demonstrate that the PS methods are an order of magnitude more efficient than the conventional methods. PS-HF was between 9 and 26 times faster than conventional integral technology, and PS-DFT (Becke three-parameter Lee-Yang-Parr) was between 6 and 21 times faster.

Molecular (hyper)polarizabilities computed by pseudospectral methods.

We have developed algorithms based on pseudospectral (PS) ab initio electronic structure methods for solving the first- and second-order Hartree-Fock/Kohn-Sham equations and evaluating molecular polarizabilities and first- and second-order hyperpolarizabilities in the spin-restricted and spin-unrestricted formalisms at the Hartree-Fock (HF) and density functional theory (DFT) levels. We carry out calculations on 50 small molecules to test the accuracy of the PS approach. Our results demonstrate that the molecular polarizability alpha computed by the PS method is essentially identical to the value obtained from conventional methods for both HF and DFT calculations, while the first-order hyperpolarizability beta and second-order hyperpolarizability gamma have mean unsigned percentage differences of 1.26% and 0.62% (HF) and 0.78% and 0.65% (DFT), respectively. We also present CPU timing comparisons between the PS and conventional methods at the 6-31 G(**) level for 14 molecules having 185 to 1185 basis functions. The timing results show that the PS method is 25 (PS-HF) and 13 (PS-DFT) times faster than the conventional method for a system with 500 basis functions. The PS methods are found scale as N(2.70) (PS-HF) and N(2.40) (PS-DFT), while the conventional methods scale as N(2.93) (PRISM-HF) and N(2.87) (PRISM-DFT), where N is the number of basis functions.

A Polarizable Force Field and Continuum Solvation Methodology for Modeling of Protein-Ligand Interactions.

A polarizable force field, and associated continuum solvation model, have been developed for the explicit purpose of computing and studying the energetics and structural features of protein binding to the wide range of ligands with potential for medicinal applications. Parameters for the polarizable force field (PFF) are derived from gas-phase ab initio calculations and then utilized for applications in which the protein binding to ligands occurs in aqueous solvents, wherein the charge distributions of proteins and ligands can be dramatically altered. The continuum solvation model is based on a self-consistent reaction field description of solvation, incorporating an analytical gradient, that allows energy minimizations (and, potentially, molecular dynamics simulations) of protein/ligand systems in continuum solvent. This technology includes a nonpolar model describing the cost of cavity formation, and van der Waals interactions, between the continuum solvent and protein/ligand solutes. Tests of the structural accuracy and computational stability of the methodology, and timings for energy minimizations of proteins and protein/ligand systems in the condensed phase, are reported. In addition, the derivation of polarizability, electrostatic, exchange repulsion, and torsion parameters from ab initio data is described, along with the use of experimental solvation energies for determining parameters for the solvation model.

Development of a polarizable force field for proteins via ab initio quantum chemistry: first generation model and gas phase tests.

We present results of developing a methodology suitable for producing molecular mechanics force fields with explicit treatment of electrostatic polarization for proteins and other molecular system of biological interest. The technique allows simulation of realistic-size systems. Employing high-level ab initio data as a target for fitting allows us to avoid the problem of the lack of detailed experimental data. Using the fast and reliable quantum mechanical methods supplies robust fitting data for the resulting parameter sets. As a result, gas-phase many-body effects for dipeptides are captured within the average RMSD of 0.22 kcal/mol from their ab initio values, and conformational energies for the di- and tetrapeptides are reproduced within the average RMSD of 0.43 kcal/mol from their quantum mechanical counterparts. The latter is achieved in part because of application of a novel torsional fitting technique recently developed in our group, which has already been used to greatly improve accuracy of the peptide conformational equilibrium prediction with the OPLS-AA force field.1 Finally, we have employed the newly developed first-generation model in computing gas-phase conformations of real proteins, as well as in molecular dynamics studies of the systems. The results show that, although the overall accuracy is no better than what can be achieved with a fixed-charges model, the methodology produces robust results, permits reasonably low computational cost, and avoids other computational problems typical for polarizable force fields. It can be considered as a solid basis for building a more accurate and complete second-generation model.