gmak: A Parameter-Space Mapping Strategy for Force-Field Calibration.

In the context of classical molecular simulations, the accuracy of a force field is highly influenced by the values of the relevant simulation parameters. In this work, a parameter-space mapping (PSM) workflow is proposed to aid in the calibration of force-field parameters, based mainly on the following features: (i) regular-grid discretization of the search space; (ii) partial sampling of the search-space grid; (iii) training of surrogate models to predict the estimates of the target properties for nonsampled parameter sets; (iv) post hoc interpretation of the results in terms of multiobjective optimization concepts; (v) attenuation of statistical errors achieved via empiric extension of the duration of the simulations; (vi) iterative search-space translation according to a user-defined scalar objective function that measures the accuracy of the force field (e.g., the weighted root-mean-square deviation of the target properties relative to the reference data). This combination of features results in a hybrid of a single- and a multiobjective optimization strategy, allowing for the approximate determination of both a local minimum of the chosen objective function and its neighboring Pareto efficient points. The PSM workflow is implemented in the extensible Python program gmak, which is made available in the Git repository at http://github.com/mssm-labmmol/gmak. Using this implementation, the PSM workflow was tested in a proof-of-concept fashion in the recalibration of the Lennard-Jones parameters of the 3-point Optimal Point Charge (OPC3) water model for compatibility with the GROMOS treatment of nonbonded interactions. The recalibrated model reproduces typical pure-liquid properties with an accuracy similar to the original OPC3 model and represents a significant improvement relative to the Simple Point Charge (SPC) model, which is the official recommendation for simulations using GROMOS force fields.

Comparison of the United- and All-Atom Representations of (Halo)alkanes Based on Two Condensed-Phase Force Fields Optimized against the Same Experimental Data Set.

The level of accuracy that can be achieved by a force field is influenced by choices made in the interaction-function representation and in the relevant simulation parameters. These choices, referred to here as functional-form variants (FFVs), include for example the model resolution, the charge-derivation procedure, the van der Waals combination rules, the cutoff distance, and the treatment of the long-range interactions. Ideally, assessing the effect of a given FFV on the intrinsic accuracy of the force-field representation requires that only the specific FFV is changed and that this change is performed at an optimal level of parametrization, a requirement that may prove extremely challenging to achieve in practice. Here, we present a first attempt at such a comparison for one specific FFV, namely the choice of a united-atom (UA) versus an all-atom (AA) resolution in a force field for saturated acyclic (halo)alkanes. Two force-field versions (UA vs AA) are optimized in an automated way using the CombiFF approach against 961 experimental values for the pure-liquid densities ρliq and vaporization enthalpies ΔHvap of 591 compounds. For the AA force field, the torsional and third-neighbor Lennard-Jones parameters are also refined based on quantum-mechanical rotational-energy profiles. The comparison between the UA and AA resolutions is also extended to properties that have not been included as parameterization targets, namely the surface-tension coefficient γ, the isothermal compressibility κT, the isobaric thermal-expansion coefficient αP, the isobaric heat capacity cP, the static relative dielectric permittivity ϵ, the self-diffusion coefficient D, the shear viscosity η, the hydration free energy ΔGwat, and the free energy of solvation ΔGche in cyclohexane. For the target properties ρliq and ΔHvap, the UA and AA resolutions reach very similar levels of accuracy after optimization. For the nine other properties, the AA representation leads to more accurate results in terms of η; comparably accurate results in terms of γ, κT, αP, ϵ, D, and ΔGche; and less accurate results in terms of cP and ΔGwat. This work also represents a first step toward the calibration of a GROMOS-compatible force field at the AA resolution.

Simultaneous parametrization of torsional and third-neighbor interaction terms in force-field development: The LLS-SC algorithm.

The calibration of torsional interaction terms by fitting relative gas-phase conformational energies against their quantum-mechanical values is a common procedure in force-field development. However, much less attention has been paid to the optimization of third-neighbor nonbonded interaction parameters, despite their strong coupling with the torsions. This article introduces an algorithm termed LLS-SC, aimed at simultaneously parametrizing torsional and third-neighbor interaction terms based on relative conformational energies. It relies on a self-consistent (SC) procedure where each iteration involves a linear least-squares (LLS) regression followed by a geometry optimization of the reference structures. As a proof-of-principle, this method is applied to obtain torsional and third-neighbor interaction parameters for aliphatic chains in the context of the GROMOS 53A6 united-atom force field. The optimized parameter set is compared to the original one, which has been fitted manually against thermodynamic properties for small linear alkanes. The LLS-SC implementation is freely available under http://github.com/mssm-labmmol/profiler.

Influence of the Treatment of Nonbonded Interactions on the Thermodynamic and Transport Properties of Pure Liquids Calculated Using the 2016H66 Force Field.

The effect of different treatments of the nonbonded interactions in simulations employing the recently introduced GROMOS-compatible 2016H66 force field is evaluated based on calculations carried out with the GROMACS software. This is done considering four thermodynamic and transport properties (pure liquid density, vaporization enthalpy, surface-tension coefficient, and self-diffusion constant) of 58 organic liquids representative of the chemical groups alcohol, ether, aldehyde, ketone, carboxylic acid, ester, amine, amide, thiol, sulfide, disulfide, and aromatic compounds, also including water (SPC model). A dipalmitoylphosphatidylcholine bilayer system is considered as well. The simulated properties are found to be very sensitive to the treatment of the long-range dispersion interactions, notably for the least polar systems. In general, the treatment of the long-range electrostatic or Lennard-Jones interactions using homogeneous correction terms or lattice-sum approaches yield similar results, with punctual discrepancies. The combination of a lattice-sum approach for the electrostatic interactions with a straight-cutoff truncation of the Lennard-Jones interactions at a distance of at least 1.2 nm is found to represent a good compromise setup within GROMACS for achieving compatibility with the reference results obtained using GROMOS as well as a comparable level of agreement with the experimental data. This study also reveals two potential issues with the GROMACS software, related to an incorrect calculation of the pressure when using LINCS in version 4.0.7 and an inadequate implementation of the twin-range scheme in version 5.1.2.

Ischemic preconditioning protects brain from ischemia/reperfusion injury by attenuating endoplasmic reticulum stress-induced apoptosis through PERK pathway.

OBJECTIVE: The purpose of this study was to explore the effects of cerebral ischemic preconditioning which can decrease brain ischemia/reperfusion (I/R) injury by inhibiting endoplasmic reticulum (ER) stress-induced apoptosis. MATERIALS AND METHODS: The focal cerebral ischemia rat was selected as the experimental model. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells in ischemic penumbra were assessed after cerebral reperfusion. We assessed terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells and measured the expressions of phosphorylation PERK (p-PERK), glucose-regulated protein 78 (GRP78), activating transcription factor-4 (ATF4) and caspase-12 in ischemic penumbra after cerebral reperfusion. RESULTS: We showed that the infarct sizes can be reduced due to the preconditioning under the influence of brain ischemia after reperfusion. The effect of preconditioning on the expression of ER stress proteins suggested the expressions of the 4 proteins p-PERK, ATF4, caspase-12 and GRP78 in the penumbra cortex by immunohistochemistry and Western blot increased after cerebral ischemia. Significant reduction of the number of TUNEL-positive cells was in the penumbra cortex of the preconditioning group. CONCLUSIONS: We found that cerebral ischemic preconditioning can protect the brain from I/R injury by inhibiting ER stress-induced apoptosis; the pathway of PERK is involved.

Hematopoietic stem cell transplantation for severe aplastic anemia--experience of an institute in Taiwan.

Hematopoietic stem cell transplantation (HSCT) is an accepted treatment strategy for patients with severe aplastic anemia (SAA). We report our experience in a general hospital in Taiwan. From March 1985 to July 2001, 79 consecutive SAA patients, 46 male and 33 female, with a median age of 22 (4-43) years, received 80 courses of transplantation. Cyclophosphamide and total body radiation were used for the conditioning regimen, and cyclosporine-A and methotrexate for graft-versus-host disease (GVHD) prevention. Patients were followed for a median of 39 months (from 8 days to 194 months). Myeloid and platelet engraftment occurred in a median of 15 (8-27) days and 18 (8-77) days, respectively. Three patients had primary and three patients secondary graft failure. Five patients (6.8%) had grade II-IV acute GVHD in 73 evaluable patients. Chronic GVHD occurred in 23 (34.8%) patients, with extensive stage in six. Only two patients had CMV disease. The projected 3- and 5-year overall survival rates estimated by the Kaplan-Meier method were 76.08 and 74.13%, respectively. Age at transplant, non-sibling donor, mononuclear cell dose, grade II-IV acute GVHD, interval from diagnosis to transplant, and red blood cell and platelet transfusion before transplant were poor prognostic factors for overall survival by univariate analysis. Grade II-IV acute GVHD was the only prognostic factor affecting overall survival after multivariate Cox regression analysis (P=0.040). In conclusion, SAA patients receiving HSCT have good long-term survival. The low incidence of acute GVHD in our patients may be related to ethnicity.

Treatment of hazardous sorbents generated from the adsorption of heavy metals during incineration.

The emission of heavy metals during waste incineration can be effectively reduced through the practice of employing non-toxic sorbents. These sorbents can react with toxic metals at high temperatures and create metal binding between them by various physical and chemical mechanisms. After the adsorption process, the used sorbents, which contain heavy metals, need to be desorbed to reduce their potential environmental hazards or provide reusable sorbents for economical aspect. The sorbent's adsorption efficiency is affected by different operating conditions and waste elemental compositions during incineration, which, in turn, affect their desorption characteristics. However, the effects of operating condition and waste elemental composition on the stability of heavy metals in the sorbents and the desorption efficiencies have been little studied. This study investigates the desorption characteristics of heavy metals (Cr, Pb, Cu, and Cd) from the hazardous sorbents with different extracting reagents (H(2)O, HCl, EDTA, and Na(2)S(2)O(5)). The hazardous sorbents were generated under different adsorption time and various input waste elemental compositions during incineration process.