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41.
Integrated circuit microchip system with multiplex capillary electrophoresis module for DNA analysis
In this paper, we describe the use of an integrated circuit (IC) microchip system as a detector in multiplex capillary electrophoresis (CE). This combination of multiplex capillary gel electrophoresis and the IC microchip technology represents a novel approach to DNA analysis on the microchip platform. Separation of DNA ladders using a multiplex CE microsystem of four capillaries was monitored simultaneously using the IC microchip system. The IC microchip-CE system has advantages such as low cost, rapid analysis, compactness, and multiplex capability, and has great potential as an alternative system to conventional capillary array gel electrophoresis systems based on charge-coupled device (CCD) detection. 相似文献
42.
Mehtap Işık Dorothy Levorse Ariën S. Rustenburg Ikenna E. Ndukwe Heather Wang Xiao Wang Mikhail Reibarkh Gary E. Martin Alexey A. Makarov David L. Mobley Timothy Rhodes John D. Chodera 《Journal of computer-aided molecular design》2018,32(10):1117-1138
Determining the net charge and protonation states populated by a small molecule in an environment of interest or the cost of altering those protonation states upon transfer to another environment is a prerequisite for predicting its physicochemical and pharmaceutical properties. The environment of interest can be aqueous, an organic solvent, a protein binding site, or a lipid bilayer. Predicting the protonation state of a small molecule is essential to predicting its interactions with biological macromolecules using computational models. Incorrectly modeling the dominant protonation state, shifts in dominant protonation state, or the population of significant mixtures of protonation states can lead to large modeling errors that degrade the accuracy of physical modeling. Low accuracy hinders the use of physical modeling approaches for molecular design. For small molecules, the acid dissociation constant (pKa) is the primary quantity needed to determine the ionic states populated by a molecule in an aqueous solution at a given pH. As a part of SAMPL6 community challenge, we organized a blind pKa prediction component to assess the accuracy with which contemporary pKa prediction methods can predict this quantity, with the ultimate aim of assessing the expected impact on modeling errors this would induce. While a multitude of approaches for predicting pKa values currently exist, predicting the pKas of drug-like molecules can be difficult due to challenging properties such as multiple titratable sites, heterocycles, and tautomerization. For this challenge, we focused on set of 24 small molecules selected to resemble selective kinase inhibitors—an important class of therapeutics replete with titratable moieties. Using a Sirius T3 instrument that performs automated acid–base titrations, we used UV absorbance-based pKa measurements to construct a high-quality experimental reference dataset of macroscopic pKas for the evaluation of computational pKa prediction methodologies that was utilized in the SAMPL6 pKa challenge. For several compounds in which the microscopic protonation states associated with macroscopic pKas were ambiguous, we performed follow-up NMR experiments to disambiguate the microstates involved in the transition. This dataset provides a useful standard benchmark dataset for the evaluation of pKa prediction methodologies on kinase inhibitor-like compounds. 相似文献
43.
Andrea Rizzi Steven Murkli John N. McNeill Wei Yao Matthew Sullivan Michael K. Gilson Michael W. Chiu Lyle Isaacs Bruce C. Gibb David L. Mobley John D. Chodera 《Journal of computer-aided molecular design》2018,32(10):937-963
Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host–guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host–guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host–guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host–guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host–guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy. 相似文献
44.
Qingyi Yang Woodrow Burchett Gregory S. Steeno Shuai Liu Mingjun Yang David L. Mobley Xinjun Hou 《Journal of computational chemistry》2020,41(3):247-257
Pairwise-based methods such as the free energy perturbation (FEP) method have been widely deployed to compute the binding free energy differences between two similar host–guest complexes. The calculated pairwise free energy difference is either directly adopted or transformed to absolute binding free energy for molecule rank ordering. We investigated, through both analytic derivations and simulations, how the selection of pairs in the experiment could impact the overall prediction precision. Our studies showed that (1) the estimated absolute binding free energy () derived from calculated pairwise differences (ΔΔG) through weighted least squares fitting is more precise in prediction than the pairwise difference values when the number of pairs is more than the number of ligands and (2) prediction precision is influenced by both the total number of pairs and the specifically selected pairs, the latter being critically important when the number of calculated pairs is limited. Furthermore, we applied optimal experimental design in pair selection and found that the optimally selected pairs can outperform randomly selected pairs in prediction precision. In an illustrative example, we showed that, upon weighing ligand structure similarity into design optimization, the weighted optimal designs are more efficient than the literature reported designs. This work provides a new approach to assess retrospective pairwise-based prediction results, and a method to design new prospective pairwise-based experiments for molecular lead optimization. © 2019 Wiley Periodicals, Inc. 相似文献
45.
Mobley DL 《Journal of computer-aided molecular design》2012,26(1):93-95
Molecular simulations see widespread and increasing use in computation and molecular design, especially within the area of
molecular simulations applied to biomolecular binding and interactions, our focus here. However, force field accuracy remains
a concern for many practitioners, and it is often not clear what level of accuracy is really needed for payoffs in a discovery
setting. Here, I argue that despite limitations of today’s force fields, current simulation tools and force fields now provide
the potential for real benefits in a variety of applications. However, these same tools also provide irreproducible results
which are often poorly interpreted. Continued progress in the field requires more honesty in assessment and care in evaluation
of simulation results, especially with respect to convergence. 相似文献
46.
INTRODUCTION In this third part of a review on chemometrics in spectroscopy we will describe a recent methodology that has attracted increasing interest in spectroscopy. namely multi-way analysis. The application of multi-way analysis in spectroscopy is still relatively new. hence many methodological improvements are being investigated currently. Part of thls review will also be used to describe the algorithmic improvements gained the last decade. 相似文献
47.
Lonzaga JB Raymond JL Mobley J Gaitan DF 《The Journal of the Acoustical Society of America》2011,129(2):597-603
The purpose of this paper is to report on the suppression of an approximately radial (radially symmetric) acoustic mode by an elastic mode of a water-filled, spherical shell resonator. The resonator, which has a 1-in. wall thickness and a 9.5-in. outer diameter, was externally driven by a small transducer bolted to the external wall. Experiments showed that for the range of drive frequencies (19.7-20.6 kHz) and sound speeds in water (1520-1570 m/s) considered in this paper, a nonradial (radially nonsymmetric) mode was also excited, in addition to the radial mode. Furthermore, as the sound speed in the liquid was changed, the resonance frequency of the nonradial mode crossed with that of the radial one and the amplitude of the latter was greatly reduced near the crossing point. The crossing of the eigenfrequency curves of these two modes was also predicted theoretically. Further calculations demonstrated that while the radial mode is an acoustic one associated with the interior fluid, the nonradial mode is an elastic one associated with the shell. Thus, the suppression of the radial acoustic mode is apparently caused by the overlapping with the nonradial elastic mode near the crossing point. 相似文献
48.
Bergazin Teresa Danielle Tielker Nicolas Zhang Yingying Mao Junjun Gunner M. R. Francisco Karol Ballatore Carlo Kast Stefan M. Mobley David L. 《Journal of computer-aided molecular design》2021,35(7):771-802
Journal of Computer-Aided Molecular Design - The Statistical Assessment of Modeling of Proteins and Ligands (SAMPL) challenges focuses the computational modeling community on areas in need of... 相似文献
49.
Sukanya Sasmal La El Khoury David L. Mobley 《Journal of computer-aided molecular design》2020,34(2):163-177
The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand Challenge 4 (GC4), which focused on predicting the binding poses and affinity ranking for compounds targeting the $$\beta$$-amyloid precursor protein (BACE-1). Our ligand similarity-based protocol using HYBRID (OpenEye Scientific Software) successfully identified poses close to the native binding mode for most of the ligands with less than 2 Å RMSD accuracy. Furthermore, we compared the performance of our HYBRID-based approach to that of AutoDock Vina and DOCK 6 and found that using a reference ligand to guide the docking process is a better strategy for pose prediction and helped HYBRID to perform better here. We also conducted end-point free energy estimates on molecules dynamics based ensembles of protein-ligand complexes using molecular mechanics combined with generalized Born surface area method (MM-GBSA). We found that the binding affinity ranking based on MM-GBSA scores have poor correlation with the experimental values. Finally, the main lessons from our participation in D3R GC4 are: (i) the generation of the macrocyclic conformers is a key step for successful pose prediction, (ii) the protonation states of the BACE-1 binding site should be treated carefully, (iii) the MM-GBSA method could not discriminate well between different predicted binding poses, and (iv) the MM-GBSA method does not perform well at predicting protein–ligand binding affinities here. 相似文献
50.
G. Conforto M.A. Kramer D. Underwood R.M. Mobley A.W. Key R. Prepost D.H. Tompkins M.S. Witherell 《Physics letters. [Part B]》1973,45(2):154-156
The missing mass spectrum in the region of the A?2 has been measured in the reaction π?p→X?p at 6.0 GeV/c in the interval 0.27 <|t|<0.42 (GeV/c)2, with an optical spark chamber system which simultaneously observed the decay X?→ηπ?. A signal of 230 events above background per five MeV interval is observed at the A2 peak, with a signal-to-background ratio of greater than 1:1. A single D-wave Breit-Wigner distribution with a quadratic background gives a good fit to the data, yielding the parameters M0=(1.324±0.003) GeV/c2 and Γ0=(0.104±0.009) GeV/c2. The spectrum is incompatible with a dipole shape. 相似文献