Large Partition Research Articles

Transient diffusion from high-capacity solute beacons

A useful protocol for maintaining long-lasting solute gradients involves a large post (“beacon”) which tends to associate with the solute in the surrounding solution. By replacing that solution with a clean one, solute diffuses out from the beacon. This transient process is significantly slowed down when the partition coefficient is large. The associated slow equilibration is naturally modeled using a quasi-steady description, with the diffusion equation being approximated by Laplace’s equation. This simplification, however, results in an ill-posed problem in the two-dimensional geometries representative of realistic experiments. This failure has to do with the breakdown of the quasi-steady description at large distances away from the beacon. The singular limit of large partition coefficient is handled here using matched asymptotic expansions.

Sustained Intracellular Raltegravir Depots Generated with Prodrugs Designed for Nanoparticle Delivery.

Polymeric nanocarriers have been extensively used to improve the delivery of hydrophobic drugs, but often provide low encapsulation efficiency and percent loading for hydrophilic compounds. In particular, insufficient loading of hydrophilic antiretroviral drugs such as the integrase inhibitor raltegravir (RAL) has limited the development of sustained-release therapeutics or prevention strategies against HIV. To address this, we developed a generalizable prodrug strategy using RAL as a model where loading, release and subsequent hydrolysis can be tuned by promoiety selection. Prodrugs with large partition coefficients increased the encapsulation efficiency up to 25-fold relative to RAL, leading to significant dose reductions in antiviral activity assays. The differential hydrolysis rates of these prodrugs led to distinct patterns of RAL availability and observed antiviral activity. We also developed a method to monitor the temporal distribution of both prodrug and RAL in cells treated with free prodrug or prodrug-NPs. Results of these studies indicated that prodrug-NPs create an intracellular drug reservoir capable of sustained intracellular drug release. Overall, our results suggest that the design of prodrugs for specific polymeric nanocarrier systems could provide a more generalized strategy to formulate physicochemically diverse hydrophilic drugs with a number of biomedical applications.

Methanol linear gradient counter-current chromatography for the separation of natural products: Sinopodophyllum hexandrum as samples

Counter-current chromatography (CCC) is a unique, liquid-liquid partition chromatography process. Both the mobile and stationary phases are liquids, so no solid support matrix is used. CCC has gained wide acceptance as a preparative technique in a variety of fields. Because the mobile and stationary phases are both liquids, gradient elution is difficult to perform with CCC. Phase equilibrium must be maintained, so any change in the composition of one phase may induce a compositional change in the other. In this work, a new linear gradient elution method was developed for CCC. Biphasic solvent systems containing heptane, ethyl acetate, methanol, and water (HepEMWat) in various ratios were prepared and used to optimize both isocratic and linear gradient CCC separation with methanol. We first separated a test mixture of four standard compounds with partition coefficients ranging from 0.8 to 7.8. The separation resembled a reversed-phase process, and elution was performed while progressively decreasing the polarity of the mobile phase. Target molecules with small partition coefficients eluted first in the lower phase of the optimized HepEMWat solvent system. Elution of constituents with large partition coefficients was quite slow under isocratic conditions. Separation time was significantly reduced when elution was performed with a linear gradient using methanol and the optimal HepEMWat system. Elution with a 3:7:4:6 (v/v/v/v) HepEMWat system took approximately 200 min. This included an 80-min isocratic step, followed by gradient elution with methanol from 0% to 30%. The optimized methanol linear gradient CCC method was then used to separate a complex mixture of natural products isolated from Sinopodophyllum hexandrum (Royle) Ying roots. Twelve compounds with a wide range of polarities were well-resolved in a single separation. We have developed a convenient and cost-effective strategy for the separation of complex mixtures. No tedious mobile phase preparation step is required. The volume of unused mobile phase is minimal, so little solvent is wasted. The method is an important advance for the separation of mixtures that contain many compounds with a large range of polarities and partition coefficients, which are common features of natural products.

The Relative Importance of Modeling Site Pattern Heterogeneity Versus Partition-Wise Heterotachy in Phylogenomic Inference.

Large taxa-rich genome-scale data sets are often necessary for resolving ancient phylogenetic relationships. But accurate phylogenetic inference requires that they are analyzed with realistic models that account for the heterogeneity in substitution patterns amongst the sites, genes and lineages. Two kinds of adjustments are frequently used: models that account for heterogeneity in amino acid frequencies at sites in proteins, and partitioned models that accommodate the heterogeneity in rates (branch lengths) among different proteins in different lineages (protein-wise heterotachy). Although partitioned and site-heterogeneous models are both widely used in isolation, their relative importance to the inference of correct phylogenies has not been carefully evaluated. We conducted several empirical analyses and a large set of simulations to compare the relative performances of partitioned models, site-heterogeneous models, and combined partitioned site heterogeneous models. In general, site-homogeneous models (partitioned or not) performed worse than site heterogeneous, except in simulations with extreme protein-wise heterotachy. Furthermore, simulations using empirically-derived realistic parameter settings showed a marked long-branch attraction (LBA) problem for analyses employing protein-wise partitioning even when the generating model included partitioning. This LBA problem results from a small sample bias compounded over many single protein alignments. In some cases, this problem was ameliorated by clustering similarly-evolving proteins together into larger partitions using the PartitionFinder method. Similar results were obtained under simulations with larger numbers of taxa or heterogeneity in simulating topologies over genes. For an empirical Microsporidia test data set, all but one tested site-heterogeneous models (with or without partitioning) obtain the correct Microsporidia+Fungi grouping, whereas site-homogenous models (with or without partitioning) did not. The single exception was the fully partitioned site-heterogeneous analysis that succumbed to the compounded small sample LBA bias. In general unless protein-wise heterotachy effects are extreme, it is more important to model site-heterogeneity than protein-wise heterotachy in phylogenomic analyses. Complete protein-wise partitioning should be avoided as it can lead to a serious LBA bias. In cases of extreme protein-wise heterotachy, approaches that cluster similarly-evolving proteins together and coupled with site-heterogeneous models work well for phylogenetic estimation.

A scalable network-aware framework for cloud monitoring orchestration

Monitoring components are implanted in clouds to evaluate performance, detect the failures, and assess component interactions by message analysis. In this paper, we propose Monitoring as a Service (MaaS) installed across its software defined network in the cloud. All switches in datacenter only forward traffic. Specific SDN application on top of the network controller has been implemented in order to orchestrate multiple network tenants monitoring needs. Applications declare the required observation for traffics and their specific monitoring needs to the Maas. Therefore, a set of virtual monitoring functions (vMF) are prescribed to be placed in datacenter for flows. An optimal placement algorithm places vMF with respect to the network and computing utilization maximization objectives. Network objective refers to minimize traffic delay for flows needed to be monitored and computing objective expresses balancing nodes computing resources. The optimal placement of virtual network functions is known to be an NP-hard problem. Compared to the existing work, we discovered different problem which how a vMF can be split into smaller pieces to decrease the total placement cost for a set of flows required, based on four patterns: free, parser-collocation, job-collocation, and full-collocation. Moreover, we proposed three heuristics to make our placement algorithm scalable for a large network, called, chain partitioning, topology partitioning, and zoning. We show the feasibility of our approach in a large dataset consists of 540k nodes and 11.5M edges, with about 40 requests (flows) at the same time. Furthermore, the proposed solution saves at least 20 percent of total monitoring cost, in average, compared to the latest related work.

Removal of perfluorooctanoic acid from water using calcined hydrotalcite – A mechanistic study

Calcined hydrotalcite (CHT) was evaluated for its potential removal of perfluorooctanoic acid (PFOA) from water in this study. The uptake of PFOA by CHT could be as high as 1587 mg/g (ca. 3.8 mmol/g), slightly larger than the anion exchange capacity (AEC) of the hydrotalcite (HT). Such a high removal was fast and pH independent, suggesting the versatile use of CHT. Due to the structural memory effect of HT, the removal involved adsorption of PFOA during HT recovery and intercalation of PFOA into the interlayer of restructured HT at low and high initial concentrations, respectively. Limited by the specific surface area and AEC, the intercalated PFOA would form a vertical bilayer or admicelle conformation. As such, the HT intercalated with PFOA became one-layer stacking with a basal spacing of 2.04 nm in contrast to the 3R polytype of recovered HT having a layer thickness of 0.78 nm, as confirmed by X-ray diffraction, thermogravimetric, and infra-red analyses. Due to its high PFOA removal capacity and large partitioning coefficient, the amount of CHT used, thus, the disposal of PFOA-laden solid could be minimized.

A 2-D simulation study on CO2 soluble surfactant for foam enhanced oil recovery

This paper probes the transport of CO2 soluble surfactant for foaming in porous media. We numerically investigate the effect of surfactant partitioning between the aqueous phase and the gaseous phase on foam transport for subsurface applications when the surfactant is injected in the CO2 phase. A 2-D reservoir simulation is developed to quantify the effect of surfactant partition coefficient on the displacement conformance and CO2 sweep efficiency. A texture-implicit local-equilibrium foam model is embedded to describe how the partitioning of surfactant between water and CO2 affects the CO2 foam mobility control when surfactant is injected in the CO2 phase. We conclude that when surfactant has approximately equal affinity to both the CO2 and the water, the transport of surfactant is in line with the gas propagation and therefore the sweep efficiency is maximized. Too high affinity to water (small partition coefficient) results in surfactant retardation whereas too high affinity to CO2 (large partition coefficient) leads to weak foam and insufficient mobility reduction. This work sheds light upon the design of water-alternating-gas-plus-surfactant-in-gas (WAG+S) process to improve the conventional foam process with surfactant-alternating-gas (SAG) injection mode during which significant amount of surfactant could possibly drain down by gravity before CO2 slugs catch up to generate foam in situ the reservoir.

Low Power Motion Estimation Algorithm and Architecture of HEVC/H.265 for Consumer Applications

High-quality videos like high-definition (HD) and ultra HD became an essential requirement in recent applications such as security surveillance, television system, etc. However, due to increase in resolution of the videos, the volume of visual information data increases significantly, which became a challenge for storage, transmission and processing the HD video data. The new video compression standard, high efficient video coding (HEVC), achieved two-fold video efficiency improvements as compared to H.264/AVC using efficient compression techniques. Motion estimation (ME) is one of the computationally intensive blocks in video CODEC. In HEVC, the complexity of ME further increases due to a large processing unit and flexible partitioning of the prediction unit (PU). In this paper, we proposed a low power ME algorithm and architecture of the HEVC for consumer applications. The proposed algorithm and architecture utilizes sub-sampling, data reuse, pixel truncation and adaptive search range techniques for reducing the computational power. Simulations result shows that the proposed ME algorithm requires an average of 53.82% fewer search points as compared to the reference software HM with a small degradation in PSNR and little increment in bit-rate. The proposed architecture is simulated and synthesized using standard 90 nm technology. The proposed ME architecture can process $3840\times2160$ @ 30 fps video sequences with only 4.5193 mm2 of the area and 8.192 KB of SRAM. The operating frequency of the proposed architecture is 250 MHz with 151.7619 mW of power.

Ductile and intergranular brittle fracture in a two-step quenching and partitioning steel

A two-step quenching and partitioning steel exhibits ductile fracture under uniaxial tension and unexpectedly intergranular brittle fracture in the case of pre-cracked configuration. A gradual retained austenite-to-martensite transformation because of low stress triaxiality under uniaxial tension, leads to ductile fracture with voids formation between fresh and tempered martensite resulting from the large strain partitioning and localization. When the retained austenite fast transforms to martensite in the near crack tip region because of high stress triaxiality, intergranular fracture is promoted by the high maximum principal stress level and by the formation of brittle martensite necklace along tempered martensitic packet boundaries.

Performance innovations in the IBM z14 platform

The IBM z14 platform brings together numerous innovations that collectively provide considerable performance gains over prior designs for the full spectrum of modern workloads being run on today's enterprise systems. These workloads range from traditional online transaction processing and batch workloads to Linux-based and cloud-based workloads, leveraging advances in analytics, mobile transaction processing, social data mining, cognitive applications, security (blockchain), and other areas. The performance gains in the z14 platform required advancements in the processor hardware microarchitecture, physical design, and instruction-set architecture, as well as in the firmware and hypervisor stacks. The result is a comprehensive platform solution that enables efficient multiprocessor scaling for large single-image partitions and mixed-workload multipartition environments within a single platform, while remaining responsive to the “bursty” demands of batch and transaction-based workloads. The performance gains present in the z14 are a direct result of the collaborative efforts between diverse teams within IBM working together to produce advancements in hardware, firmware, and software that outpace the gains of the individual contributions. In this paper, we discuss these results with a focus on the client value delivered through system performance and workload responsiveness.

Improving Recommendation Techniques by Deep Learning and Large Scale Graph Partitioning

Recommendation is very crucial technique for social networking sites and business organizations. It provides suggestions based on users’ personalized interest and provide users with movies, books and topics links that would be most suitable for them. It can improve user effectiveness and business revenue by approximately 30%, if analyzed in intelligent manner. Social recommendation systems for traditional datasets are already analyzed by researchers and practitioners in detail. Several researchers have improved recommendation accuracy and throughput by using various innovative approaches. Deep learning has been proven to provide significant improvements in image processing and object recognition. It is machine learning technique where hidden layers are used to improve outcome. In traditional recommendation techniques, sparsity and cold start are limitations which are due to less user-item interactions. This can be removed by using deep learning models which can improve user-item matrix entries by using feature learning. In this paper, various models are explained with their applications. Readers can identify best suitable model from these deep learning models for recommendation based on their needs and incorporate in their techniques. When these recommendation systems are deployed on large scale of data, accuracy degrades significantly. Social big graph is most suitable for large scale social data. Further improvements for recommendations are explained with the use of large scale graph partitioning. MAE (Mean Absolute Error) and RMSE (Root Mean Squared Error) are used as evaluation parameters which are used to prove better recommendation accuracy. Epinions, MovieLens and FilmTrust datasets are also shown as most commonly used datasets for recommendation purpose.

Responses of field evapotranspiration to the changes of cropping pattern and groundwater depth in large irrigation district of Yellow River basin

To solve the problems of decreasing water resources from the Yellow River, the renovation project of water-saving and controlling water distribution was implemented in the Hetao Irrigation District of North China since 1999. The local hydrological cycle is expected to be influenced or changed during the past fifteen years through the project. Jiefangzha Irrigation Region, the second large partition of the Hetao Irrigation District, was selected as the typical area to explore the relationship between agricultural water consumption, water distribution, cropping pattern and changing groundwater level. In this paper, the SEBS (Surface Energy Balance System) model and the ESTARFM (Enhanced Spatial and Temporal Adaptive Reflectance Fusion Model) algorithm were applied to produce daily field-scale evapotranspiration (ET) based on Landsat and MODIS data from 2000 to 2015 at intervals. The results indicate that the cropping pattern had changed greatly, while the water table descended through the years. The total agriculture ET stayed relatively stable, with the average annual consumption of 8.9×108m3. The temporal variation of agriculture ET was not obviously sensitive to the adjustment of cropping pattern. There was no significant difference in April–October ET for different crops, in spite of the clear distinction of ET in each crop-specific growing season. The spatial distribution of agricultural ET did not change in spite of the great adjustment of cropping pattern during fifteen years, which has a close inverse correlation with the groundwater depth. Groundwater depth descended from 1.76m to 2.33m during the operation period of the water-saving project, which might reduce the soil evaporation and have a positive effect on soil salinization effectively. Meanwhile, the net irrigation water use efficiency was improved from 0.59 to 0.66. These effects indicate the positive impact of the implemented water-saving renovation project on water management and environment. However, the actual crop coefficient Kc,a decreased slightly with the gradually increasing reference evapotranspiration, indicating possible drought stress as an effect of the continuing reduction of the availability of net irrigation water and declining groundwater table.

Lagrangian relaxation versus genetic algorithm based metaheuristic for a large partitioning problem

This paper is concerned with a partitioning problem. One of the applications, and the motivation for this research, is the problem of class formation for training and retraining sessions at large electricity distributors. Two different approaches are developed. One is based on the Quadratic Multiple Knapsack formulation and Lagrangian relaxation. The other is a matheuristic developed as an amalgamation of Genetic Algorithms and Integer Programming. The approaches are tested by means of computational experiments. Both heuristics outperformed the direct application of quadratic programming, with the Lagrangian relaxation based approach performing the best on average, and the Genetic Algorithm based approach performing the best on the larger test cases.

Honey they shrank the food! An integrative study of the impact of food granularity and its operationalization mode on consumption

Larger portions of tempting food spur consumption, yet the question remains whether altering food granularity (i.e., dividing a fixed portion into more, smaller versus fewer, larger partitions) also drives consumption. As current insights on the impact of food granularity on consumption are contradictory, this paper offers clarification by zooming in on the different ways in which food granularity has been operationalized in extant research. One can achieve a finer (vs. coarser) food granularity either by partitioning food into more, smaller morsels (vs. fewer larger morsels), or by grouping similarly sized food morsels together into more, smaller packages (vs. fewer, larger packages). Hence, this article introduces the operationalization mode of food granularity (i.e., partitioning vs. grouping) as a variable moderating the effect of food granularity (i.e., fine vs. coarse) on consumption. Consumers are expected to eat less when tempting foods are partitioned in more, smaller portions (as opposed to fewer, larger portions). However, consumers eat more when such tempting foods are grouped into more, smaller packages (as opposed to fewer, larger packages). Both a meta-analytic review (Study 1) and a lab experiment (Study 2) confirm this anticipated interaction effect. In addition, Study 2 shows that the extent of experienced self-control conflict underlies this combined effect of food granularity and operationalization mode on consumption. This study also shows that (un)restrained eating is an additional moderator of the interaction. These findings highlight that the manner used to divide tempting foods has important implications for consumption, which is relevant in light of the current obesity epidemic.

Partition function and astronomical observation of interstellar isomers: Is there a link?

The unsuccessful astronomical searches for some important astrophysical and astrobiological molecules have been linked to the large partition function of these molecules. This letter reports an extensive investigation of the relationship between partition function and astronomical observation of interstellar isomers using high level quantum chemical calculations. 120 molecules from 30 different isomeric groups have been considered. Partition function and thermodynamic stabilities are determined for each set of isomeric species. From the results, there is no direct correlation between partition function and astronomical observation of the same isomeric species. Though interstellar formations processes are generally controlled by factors like kinetics, thermodynamics, formation and destruction pathways. However, the observation of the isomers seems to correlate well with thermodynamics. For instance, in all the groups considered, the astronomically detected isomers are the thermodynamically most stable molecules in their respective isomeric groups. The implications of these results in accounting for the limited number of known cyclic interstellar molecules, unsuccessful searches for amino acid and the possible molecules for astronomical observations are discussed.

Design and Fabrication of Unequal Power Divider using Impedance Limitation Method

Objectives: In this letter, the achievability of an unequal power divider utilizing a microstrip innovation as a part of the P/UHF band is designed. Methods/Statistical Analysis: Unequal power divider with 3-alternatives/approaches is composed in this research work, these are traditional microstrip configuration, power divider with input transformer and discretionary outline impedance (A-arbitary) is acquainted with control high impedance values and Power divider with general outline comparisons (Determination of Z1 or Z2 with required Impedances). Findings: At long last Power divider with general outline comparisons is figured it out. In this case the impedance of any one of the quarter wave impedance transmission line chosen is 30/35Ω which is most appropriate for impedance confinement of 10-60 ohm with a large power partitioning proportion radar applications where the side projection levels are most negative required. The unequal amplitudes of the 8-way power divider is designed utilizing Taylors 1-parameter method to get the side projections levels – 17 dB down from the fundamental beam. Application/Improvements: The 2-way and 8-way power divider was simulated using Method of Moments based Zealand IE3D software (MOM) an aggregate bandwidth of 40MHz was accomplished at an resonant frequency 0.43GHz. The simulated 2-way and 8-way unequal power divider is simulated and results are given. A prototype of 2-way unequal power divider with power levels P1 and P2 are 0.79622 and 0.89352 with power ratio of 1.1222 is fabricated to verify our proposed design. Measured results are given good agreement with simulated results to confirm our proposed design.

ParB Partition Proteins: Complex Formation and Spreading at Bacterial and Plasmid Centromeres.

In bacteria, active partition systems contribute to the faithful segregation of both chromosomes and low-copy-number plasmids. Each system depends on a site-specific DNA binding protein to recognize and assemble a partition complex at a centromere-like site, commonly called parS. Many plasmid, and all chromosomal centromere-binding proteins are dimeric helix-turn-helix DNA binding proteins, which are commonly named ParB. Although the overall sequence conservation among ParBs is not high, the proteins share similar domain and functional organization, and they assemble into similar higher-order complexes. In vivo, ParBs “spread,” that is, DNA binding extends away from the parS site into the surrounding non-specific DNA, a feature that reflects higher-order complex assembly. ParBs bridge and pair DNA at parS and non-specific DNA sites. ParB dimers interact with each other via flexible conformations of an N-terminal region. This review will focus on the properties of the HTH centromere-binding protein, in light of recent experimental evidence and models that are adding to our understanding of how these proteins assemble into large and dynamic partition complexes at and around their specific DNA sites.

Impacts of Plant Community Changes on Soil Carbon Contents in Northeastern Illinois

ABSTRACTLand-cover changes not only affect regional climates through alteration in surface energy and water balance, but also affect key ecological processes, such as carbon (C) cycling and sequestration in plant ecosystems. The object of this study was to investigate the effects of land-cover changes on the distribution of soil organic carbon (SOC) contents under four plant community types (deciduous forests, pine forests, mixed pine-deciduous forests, and prairies) in northeastern Illinois, USA. Soil samples were collected from incremental soil depths (0–10, 10–20, 20–30, and 30–50 cm) under the studied plant communities. The results showed that SOC concentration decreased with increases of soil depth in the studied forests and prairies. No significant differences of SOC concentrations were found at the upper soil layers (0–10 cm) among the four plant types. However, SOC concentrations were statistically higher at the lower soil depth (30–40 cm) in prairies than in other three forest types. The SOC storage (0–40 cm soil depth) was reduced in an order prairies (250.6) > mixed pine-deciduous forests (240.7) > pine forests (190.1) > deciduous forests (163.4 Mg/ha). The characteristics of relative short life cycle, restively high turnover rate of roots, and large partition of photosynthetic production allocated to belowground were likely attributed to the higher accumulation of C in soils in tallgrass prairies than in forests. Our data indicated the conversion of native tallgrass prairies to pure forest plantations resulted in a considerable decline of SOC storage. Results suggest that land-cover changes have a significant impact on SOC storage and sequestration in plant ecosystems.

EFFICIENT IMAGE RETRIEVAL IN BIG DATABASE USING MULTI FEATURE DESCRIPTOR

Image processing is processing of images by using any form of signal processing using mathematical operations for which an image or a video is input. The image processing output may be an image or a set of parameters based on the image. An image retrieval system for a large database of digital images is a computer system for searching, retrieving and browsing image and obtaining most similar images. From the retrieved image multi features like Color Histogram, HOG Transform, Local Binary feature and Gist. Each of these features need to transfer by applying Heat Kernel function to generate range with each of this feature mentioned to a range form a multiview hash and put it in hash table. Calculate hash for the image and this hash can be map for different images also. The existing method for image retrieval is Hashing technology. Hashing is used to index and retrieve items in a database because it is faster to find the items using the shorter hashed key than to find it using the original value. For most hashing strategies, the performance of retrieval vigorously relies upon the decision of the high-dimensional component descriptor. The disadvantage is Curse of dimensionality and does not search faster. The proposed methods are Multi Feature Descriptor and Multiview alignment Hashing. Multiview alignment hashing approach based on regularized kernel nonnegative matrix factorization(NMF), which can find a compact representation uncovering the hidden semantics and simultaneously respecting the joint probability distribution of data and it can easily searches the similar images in less interval of time and it is effective.. Hash within Hash technology is the future enhancement, the hash size is large partitioning the hash and obtaining the efficient result.

Converging ligand-binding free energies obtained with free-energy perturbations at the quantum mechanical level.

In this article, the convergence of quantum mechanical (QM) free‐energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa‐acid deep‐cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in the QM calculations (158–224 atoms). We use single‐step exponential averaging (ssEA) and the non‐Boltzmann Bennett acceptance ratio (NBB) methods to estimate QM/MM free energy with the semi‐empirical PM6‐DH2X method, both based on interaction energies. We show that ssEA with cumulant expansion gives a better convergence and uses half as many QM calculations as NBB, although the two methods give consistent results. With 720,000 QM calculations per transformation, QM/MM free‐energy estimates with a precision of 1 kJ/mol can be obtained for all eight relative energies with ssEA, showing that this approach can be used to calculate converged QM/MM binding free energies for realistic systems and large QM partitions. © 2016 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.