Assessing and Ensuring GOES-R Magnetometer Accuracy

The GOES-R magnetometer subsystem accuracy requirement is 1.7 nanoteslas (nT). During quiet times (100 nT), accuracy is defined as absolute mean plus 3 sigma. During storms (300 nT), accuracy is defined as absolute mean plus 2 sigma. Error comes both from outside the magnetometers, e.g. spacecraft fields and misalignments, as well as inside, e.g. zero offset and scale factor errors. Because zero offset and scale factor drift over time, it will be necessary to perform annual calibration maneuvers. To predict performance before launch, we have used Monte Carlo simulations and covariance analysis. Both behave as expected, and their accuracy predictions agree within 30%. With the proposed calibration regimen, both suggest that the GOES-R magnetometer subsystem will meet its accuracy requirements

Assessing and Ensuring GOES-R Magnetometer Accuracy

The GOES-R magnetometer accuracy requirement is 1.7 nanoteslas (nT). During quiet times (100 nT), accuracy is defined as absolute mean plus 3 sigma. During storms (300 nT), accuracy is defined as absolute mean plus 2 sigma. To achieve this, the sensor itself has better than 1 nT accuracy. Because zero offset and scale factor drift over time, it is also necessary to perform annual calibration maneuvers. To predict performance, we used covariance analysis and attempted to corroborate it with simulations. Although not perfect, the two generally agree and show the expected behaviors. With the annual calibration regimen, these predictions suggest that the magnetometers will meet their accuracy requirements

Increased Operational Availability and Simplified Operations Using Dither Gyro Scale Factor Calibration

The traditional approach to on-orbit gyro scale factor calibration has been to perform large angle rotations about each gyro axis. The maneuvers require the science instruments to be taken offline, reducing operational availability and require a significant amount of interaction from the ground. To increase operational availability and to reduce the burden on mission operators, a novel approach to gyro scale factor calibration was developed, modeled and successfully demonstrated on the Geostationary Operational Environmental Satellite (GOES-16) to estimate gyro scale factor errors to within 1500 parts per million (ppm) without taking the science instruments offline

GOES-R Dual Isolation

The Geostationary Operational Environmental Satellite-R Series (GOES-R) is the first of the next generation geostationary weather satellites, scheduled for delivery in late 2015. GOES-R represents a quantum increase in Earth and solar weather observation capabilities, with 4 times the resolution, 5 times the observation rate, and 3 times the number of spectral bands for Earth observations. With the improved resolution, comes the instrument suite's increased sensitive to disturbances over a broad spectrum 0-512 Hz. Sources of disturbance include reaction wheels, thruster firings for station keeping and momentum management, gimbal motion, and internal instrument disturbances. To minimize the impact of these disturbances, the baseline design includes an Earth Pointed Platform (EPP), a stiff optical bench to which the two nadir pointed instruments are collocated together with the Guidance Navigation & Control (GN&C) star trackers and Inertial Measurement Units (IMUs). The EPP is passively isolated from the spacecraft bus with Honeywell D-Strut isolators providing attenuation for frequencies above approximately 5 Hz in all six degrees-of-freedom. A change in Reaction Wheel Assembly (RWA) vendors occurred very late in the program. To reduce the risk of RWA disturbances impacting performance, a secondary passive isolation system manufactured by Moog CSA Engineering was incorporated under each of the six 160 Nms RWAs, tuned to provide attenuation at frequencies above approximately 50 Hz. Integrated wheel and isolator testing was performed on a Kistler table at NASA Goddard Space Flight Center. High fidelity simulations were conducted to evaluate jitter performance for four topologies: 1) hard mounted no isolation, 2) EPP isolation only, 2) RWA isolation only, and 4) dual isolation. Simulation results demonstrate excellent performance relative to the pointing stability requirements, with dual isolated Line of Sight (LOS) jitter less than 1 micron rad

GOES-16 Magnetometers Anomaly Solar-Angle Based Characterization and Correction

GOES-R launched aboard an Atlas V 541 rocket from Space Launch Complex-41 at Cape Canaveral Air Force Station, Florida, on November 19, 2016. The first satellite in the series, GOES-R, was renamed GOES-16 upon reaching geostationary orbit GOES-16 at GOES-Checkout location (89.5 degrees West Longitude) during PLT (Post-Launch Testing). The GOES-16 magnetometer boom was deployed on December 7, 2016 and magnetometer checkout began. GOES-16 replaced GOES-13 as NOAA's operational GOES-East satellite on December 18, 2017. The GOES-16 satellite operational location (GOES-East) is at 75.2 degrees West Longitude

Initial Navigation Alignment of Optical Instruments on GOES-R

Post-launch alignment errors for the Advanced Baseline Imager (ABI) and Geospatial Lightning Mapper (GLM) on GOES-R may be too large for the image navigation and registration (INR) processing algorithms to function without an initial adjustment to calibration parameters. We present an approach that leverages a combination of user-selected image-to-image tie points and image correlation algorithms to estimate this initial launch-induced offset and calculate adjustments to the Line of Sight Motion Compensation (LMC) parameters. We also present an approach to generate synthetic test images, to which shifts and rotations of known magnitude are applied. Results of applying the initial alignment tools to a subset of these synthetic test images are presented. The results for both ABI and GLM are within the specifications established for these tools, and indicate that application of these tools during the post-launch test (PLT) phase of GOES-R operations will enable the automated INR algorithms for both instruments to function as intended

Wordom: A User-Friendly Program for the Analysis of Molecular Structures, Trajectories, and Free Energy Surfaces

Wordom is a versatile, user-friendly, and efficient program for manipulation and analysis of molecular structures and dynamics. The following new analysis modules have been added since the publication of the original Wordom paper in 2007: assignment of secondary structure, calculation of solvent accessible surfaces, elastic network model, motion cross correlations, protein structure network, shortest intra-molecular and inter-molecular communication paths, kinetic grouping analysis, and calculation of mincut-based free energy profiles. In addition, an interface with the Python scripting language has been built and the overall performance and user accessibility enhanced. The source code of Wordom (in the C programming language) as well as documentation for usage and further development are available as an open source package under the GNU General Purpose License from http://wordom.sf.net. © 2010 Wiley Periodicals, Inc. J Comput Chem, 201

A flexible loop in yeast ribosomal protein L11 coordinates P-site tRNA binding

High-resolution structures reveal that yeast ribosomal protein L11 and its bacterial/archael homologs called L5 contain a highly conserved, basically charged internal loop that interacts with the peptidyl-transfer RNA (tRNA) T-loop. We call this the L11 ‘P-site loop’. Chemical protection of wild-type ribosome shows that that the P-site loop is inherently flexible, i.e. it is extended into the ribosomal P-site when this is unoccupied by tRNA, while it is retracted into the terminal loop of 25S rRNA Helix 84 when the P-site is occupied. To further analyze the function of this structure, a series of mutants within the P-site loop were created and analyzed. A mutant that favors interaction of the P-site loop with the terminal loop of Helix 84 promoted increased affinity for peptidyl-tRNA, while another that favors its extension into the ribosomal P-site had the opposite effect. The two mutants also had opposing effects on binding of aa-tRNA to the ribosomal A-site, and downstream functional effects were observed on translational fidelity, drug resistance/hypersensitivity, virus maintenance and overall cell growth. These analyses suggest that the L11 P-site loop normally helps to optimize ribosome function by monitoring the occupancy status of the ribosomal P-site

Solution structure of an alternate conformation of helix27 from Escherichia coli 16S rRNA

Helix (H)27 of 16S ribosomal (r)RNA from Escherichia coli was dubbed the “switch helix” when mutagenesis suggested that two alternative base pair registers may have distinct functional roles in the bacterial ribosome. Although more recent genetic analyses suggest that H27 conformational switching is not required for translation, previous solution studies demonstrated that the isolated E. coli H27 can dynamically convert between the 885 and 888 conformations. Here, we have solved the nuclear magnetic resonance solution structure of a locked 888 conformation. NOE and residual dipolar coupling restraints reveal an architecture that markedly differs from that of the 885 conformation found in crystal structures of the bacterial ribosome. In place of the loop E motif that characterizes the 885 conformer and that the 888 conformer cannot adopt, we find evidence for an asymmetrical A‐rich internal loop stabilized by stacking interactions among the unpaired A's. Comparison of the isolated H27 888 solution structure with the 885 crystal structure within the context of the ribosome suggests a difference in overall length of H27 that presents one plausible reason for the absence of H27 conformational switching within the sterically confining ribosome. © 2011 Wiley Periodicals, Inc. Biopolymers 95: 653–668, 2011.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86980/1/21626_ftp.pd

Identification of a common recognition center for a photoactive non-steroidal antiinflammatory drug in serum albumins of different species

[EN] The non-steroidal anti-inflammatory drug (S)-carprofen (CPF) has been used as a photoactive probe to investigate the possible existence of a common recognition center in serum albumins (SAs) of different species. The methodology involves irradiation of the CPF/SA complexes, coupled with gel filtration chromatography or proteomic analysis of the photolysates, docking and molecular dynamics simulations. Photolysis of CPF/SA complexes at = 320 nm, and gel filtration chromatography, revealed that the protein fraction still contained the drug fluorophore, in agreement with covalent attachment of the photogenerated radical intermediate CBZ to SAs. After trypsin digestion and ESI-MS/MS, the incorporation of CBZ was detected at several positions in the different albumins. Remarkably, modifications at the IB/IIIA interface were observed in all cases (Tyr452 in HSA, RbSA and RtSA and Tyr451 in BSA, PSA and SSA). The molecular basis of this common recognition, studied by docking and molecular dynamics simulation studies on the corresponding non-covalent complexes, corroborated the experimentally observed covalent modifications. Our computational studies also revealed that the previously reported displacement of CPF by (S)-ibuprofen, a site II specific drug, would be due to an allosteric effect in site II, rather than a direct molecular displacement, as expected.Financial support from the Spanish Ministry of Economy and Competiveness (CTQ2016-78875-P, SAF2016-75638-R and BES-2014-069404), Generalitat Valenciana (PROMETEO2017/075), Conselleria de Cultura, Educacion e Ordenacion Universitaria (Centro singular de investigacion de Galicia accreditation 2016-2019, ED431G/09) and the European Regional Development Fund (ERDF) is acknowledged. This work was also supported by Instituto de Salud Carlos III (ISCIII) co-funded by Fondo Europeo de Desarrollo Regional FEDER for the Thematic Networks and Co-operative Research Centres: ARADyAL (RD16/0006/0030). EL thanks the Xunta de Galicia for his postdoctoral fellowship. We are also grateful to the Centro de Supercomputacion de Galicia (CESGA) for use of the Finis Terrae II supercomputer. The proteomic analysis was performed in the proteomics facility of SCSIE University of Valencia that belongs to ProteoRed PRB2-ISCIII and is supported by grant PT13/0001, of the PE I+D+I 2013-2016, funded by ISCIII and FEDER.Molins-Molina, O.; Lence, E.; Limones-Herrero, D.; González-Bello, C.; Miranda Alonso, MÁ.; Jiménez Molero, MC. (2019). Identification of a common recognition center for a photoactive non-steroidal antiinflammatory drug in serum albumins of different species. Organic Chemistry Frontiers. 6(1):99-109. https://doi.org/10.1039/c8qo01045eS9910961Limones-Herrero, D., Pérez-Ruiz, R., Lence, E., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2017). Mapping a protein recognition centre with chiral photoactive ligands. An integrated approach combining photophysics, reactivity, proteomics and molecular dynamics simulation studies. Chemical Science, 8(4), 2621-2628. doi:10.1039/c6sc04900aO’Brien, W. M., & Bagby, G. F. (1987). Carprofen: A New Nonsteroidal Antiinflammatory Drug Pharmacology, Clinical Efficacy and Adverse Effects. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 7(1), 16-24. doi:10.1002/j.1875-9114.1987.tb03500.xCurry, S. L., Cogar, S. M., & Cook, J. L. (2005). Nonsteroidal Antiinflammatory Drugs: A Review. Journal of the American Animal Hospital Association, 41(5), 298-309. doi:10.5326/0410298LEES, P., LANDONI, M. F., Giraudel, J., & TOUTAIN, P. L. (2004). Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest. Journal of Veterinary Pharmacology and Therapeutics, 27(6), 479-490. doi:10.1111/j.1365-2885.2004.00617.xT. J. Peter , All about albumin: biochemistry, genetics and medical applications , Academic press , California , 1996He, X. M., & Carter, D. C. (1992). Atomic structure and chemistry of human serum albumin. Nature, 358(6383), 209-215. doi:10.1038/358209a0Kragh-Hansen, U., Chuang, V. T. G., & Otagiri, M. (2002). Practical Aspects of the Ligand-Binding and Enzymatic Properties of Human Serum Albumin. Biological and Pharmaceutical Bulletin, 25(6), 695-704. doi:10.1248/bpb.25.695Fasano, M., Curry, S., Terreno, E., Galliano, M., Fanali, G., Narciso, P., … Ascenzi, P. (2005). The extraordinary ligand binding properties of human serum albumin. IUBMB Life (International Union of Biochemistry and Molecular Biology: Life), 57(12), 787-796. doi:10.1080/15216540500404093Carter, D. C., & Ho, J. X. (1994). Structure of Serum Albumin. Advances in Protein Chemistry, 153-203. doi:10.1016/s0065-3233(08)60640-3Kosa, T., Maruyama, T., & Otagiri, M. (1997). Pharmaceutical Research, 14(11), 1607-1612. doi:10.1023/a:1012138604016Chang, C.-F., & Jeng, S.-R. (1995). Isolation and characterization of the female-specific protein (vitellogenin) in mature female hemolymph of the prawn Penaeus chinensis. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 112(2), 257-263. doi:10.1016/0305-0491(95)00059-3Rahman, M. H., Maruyama, T., Okada, T., Yamasaki, K., & Otagiri, M. (1993). Study of interaction of carprofen and its enantiomers with human serum albumin—I. Biochemical Pharmacology, 46(10), 1721-1731. doi:10.1016/0006-2952(93)90576-iVayá, I., Pérez-Ruiz, R., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2010). Drug–protein interactions assessed by fluorescence measurements in the real complexes and in model dyads. Chemical Physics Letters, 486(4-6), 147-153. doi:10.1016/j.cplett.2009.12.091Lhiaubet-Vallet, V., Boscá, F., & Miranda, M. A. (2006). Stereodifferentiating Drug−Biomolecule Interactions in the Triplet Excited State:  Studies on Supramolecular Carprofen/Protein Systems and on Carprofen−Tryptophan Model Dyads. The Journal of Physical Chemistry B, 111(2), 423-431. doi:10.1021/jp066968kRahman, M. H., Maruyama, T., Okada, T., Imai, T., & Otagiri, M. (1993). Study of interaction of carprofen and its enantiomers with human serum albumin—II. Biochemical Pharmacology, 46(10), 1733-1740. doi:10.1016/0006-2952(93)90577-jDivkovic, M., Pease, C. K., Gerberick, G. F., & Basketter, D. A. (2005). Hapten-protein binding: from theory to practical application in the in vitro prediction of skin sensitization. Contact Dermatitis, 53(4), 189-200. doi:10.1111/j.0105-1873.2005.00683.xJohannesson, G., Rosqvist, S., Lindh, C. H., Welinder, H., & Jönsson, B. A. G. (2001). Serum albumins are the major site for in vivo formation of hapten-carrier protein adducts in plasma from humans and guinea-pigs exposed to type-1 allergy inducing hexahydrophthalic anhydride. Clinical & Experimental Allergy, 31(7), 1021-1030. doi:10.1046/j.1365-2222.2001.01109.xLahoz, A., Hernández, D., Miranda, M. A., Pérez-Prieto, J., Morera, I. M., & Castell, J. V. (2001). Antibodies Directed to Drug Epitopes to Investigate the Structure of Drug−Protein Photoadducts. Recognition of a Common Photobound Substructure in Tiaprofenic Acid/Ketoprofen Cross-Photoreactivity. Chemical Research in Toxicology, 14(11), 1486-1491. doi:10.1021/tx0002482P. Jones , In vitro phototoxicity assays , in Principles and Practice of Skin Toxicology , ed. R. Chilcott and S. Price , John Wiley & Sons , 2008 , p. 169Merot, Y., Harms, M., & Saurat, J.-H. (1983). Photosensibilisation au carprofène (Imady®), un nouvel anti-inflammatoire non stéroïdien. Dermatology, 166(6), 301-307. doi:10.1159/000249894Roelandts, G., & Goh, C. L. (1986). Photosensitivity Associated with Carprofen. Dermatology, 172(1), 64-65. doi:10.1159/000249297Boscá, F., Marín, M. L., & Miranda, M. A. (2001). Photoreactivity of the Nonsteroidal Anti-inflammatory 2-Arylpropionic Acids with Photosensitizing Side Effects¶. Photochemistry and Photobiology, 74(5), 637. doi:10.1562/0031-8655(2001)0742.0.co;2Kerr, A. C., Muller, F., Ferguson, J., & Dawe, R. S. (2008). Occupational carprofen photoallergic contact dermatitis. British Journal of Dermatology, 159(6), 1303-1308. doi:10.1111/j.1365-2133.2008.08847.xMoser, J., Boscá, F., Lovell, W. W., Castell, J. V., Miranda, M. A., & Hye, A. (2000). Photobinding of carprofen to protein. Journal of Photochemistry and Photobiology B: Biology, 58(1), 13-19. doi:10.1016/s1011-1344(00)00115-9P.-L. Toutain , A.Ferran and A.Bousquet-Mélou , Species Differences in Pharmacokinetics and Pharmacodynamics , in Handbook of Experimental Pharmacology, Vol. 199, Comparative and Veterinary Pharmacology , ed. F. Cunningan , J. Elliot and P. Lees , Springer-Verlag , Berlin, Heidelberg , 2010Bosca, F., Encinas, S., Heelis, P. F., & Miranda, M. A. (1997). Photophysical and Photochemical Characterization of a Photosensitizing Drug:  A Combined Steady State Photolysis and Laser Flash Photolysis Study on Carprofen. Chemical Research in Toxicology, 10(7), 820-827. doi:10.1021/tx9700376Sekula, B., Ciesielska, A., Rytczak, P., Koziołkiewicz, M., & Bujacz, A. (2016). Structural evidence of the species-dependent albumin binding of the modified cyclic phosphatidic acid with cytotoxic properties. Bioscience Reports, 36(3). doi:10.1042/bsr20160089http://www.ccdc.cam.ac.uk/solutions/csd-discovery/components/gold/Sivertsen, A., Isaksson, J., Leiros, H.-K. S., Svenson, J., Svendsen, J.-S., & Brandsdal, B. O. (2014). Synthetic cationic antimicrobial peptides bind with their hydrophobic parts to drug site II of human serum albumin. BMC Structural Biology, 14(1). doi:10.1186/1472-6807-14-4Pérez-Ruíz, R., Lence, E., Andreu, I., Limones-Herrero, D., González-Bello, C., Miranda, M. A., & Jiménez, M. C. (2017). A New Pathway for Protein Haptenation by β-Lactams. Chemistry - A European Journal, 23(56), 13986-13994. doi:10.1002/chem.201702643Ghuman, J., Zunszain, P. A., Petitpas, I., Bhattacharya, A. A., Otagiri, M., & Curry, S. (2005). Structural Basis of the Drug-binding Specificity of Human Serum Albumin. Journal of Molecular Biology, 353(1), 38-52. doi:10.1016/j.jmb.2005.07.075Curry, S., Mandelkow, H., Brick, P., & Franks, N. (1998). Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nature Structural Biology, 5(9), 827-835. doi:10.1038/1869Miller, B. R., McGee, T. D., Swails, J. M., Homeyer, N., Gohlke, H., & Roitberg, A. E. (2012). MMPBSA.py: An Efficient Program for End-State Free Energy Calculations. Journal of Chemical Theory and Computation, 8(9), 3314-3321. doi:10.1021/ct300418hWang, Z., Ho, J. X., Ruble, J. R., Rose, J., Rüker, F., Ellenburg, M., … Carter, D. C. (2013). Structural studies of several clinically important oncology drugs in complex with human serum albumin. Biochimica et Biophysica Acta (BBA) - General Subjects, 1830(12), 5356-5374. doi:10.1016/j.bbagen.2013.06.032Zunszain, P. A., Ghuman, J., Komatsu, T., Tsuchida, E., & Curry, S. (2003). BMC Structural Biology, 3(1), 6. doi:10.1186/1472-6807-3-6Kelley, L. A., Mezulis, S., Yates, C. M., Wass, M. N., & Sternberg, M. J. E. (2015). The Phyre2 web portal for protein modeling, prediction and analysis. Nature Protocols, 10(6), 845-858. doi:10.1038/nprot.2015.053Vanquelef, E., Simon, S., Marquant, G., Garcia, E., Klimerak, G., Delepine, J. C., … Dupradeau, F.-Y. (2011). R.E.D. Server: a web service for deriving RESP and ESP charges and building force field libraries for new molecules and molecular fragments. Nucleic Acids Research, 39(suppl_2), W511-W517. doi:10.1093/nar/gkr288http://upjv.q4md-forcefieldtools.org/RED/Dupradeau, F.-Y., Pigache, A., Zaffran, T., Savineau, C., Lelong, R., Grivel, N., … Cieplak, P. (2010). The R.E.D. tools: advances in RESP and ESP charge derivation and force field library building. Physical Chemistry Chemical Physics, 12(28), 7821. doi:10.1039/c0cp00111bCornell, W. D., Cieplak, P., Bayly, C. I., Gould, I. R., Merz, K. M., Ferguson, D. M., … Kollman, P. A. (1995). A Second Generation Force Field for the Simulation of Proteins, Nucleic Acids, and Organic Molecules. Journal of the American Chemical Society, 117(19), 5179-5197. doi:10.1021/ja00124a002Case, D. A., Cheatham, T. E., Darden, T., Gohlke, H., Luo, R., Merz, K. M., … Woods, R. J. (2005). The Amber biomolecular simulation programs. Journal of Computational Chemistry, 26(16), 1668-1688. doi:10.1002/jcc.20290Wang, J., Wolf, R. M., Caldwell, J. W., Kollman, P. A., & Case, D. A. (2004). Development and testing of a general amber force field. Journal of Computational Chemistry, 25(9), 1157-1174. doi:10.1002/jcc.20035Wang, J., Wang, W., Kollman, P. A., & Case, D. A. (2006). Automatic atom type and bond type perception in molecular mechanical calculations. Journal of Molecular Graphics and Modelling, 25(2), 247-260. doi:10.1016/j.jmgm.2005.12.005Gordon, J. C., Myers, J. B., Folta, T., Shoja, V., Heath, L. S., & Onufriev, A. (2005). H++: a server for estimating pKas and adding missing hydrogens to macromolecules. Nucleic Acids Research, 33(Web Server), W368-W371. doi:10.1093/nar/gki464http://biophysics.cs.vt.edu/H++Götz, A. W., Williamson, M. J., Xu, D., Poole, D., Le Grand, S., & Walker, R. C. (2012). Routine Microsecond Molecular Dynamics Simulations with AMBER on GPUs. 1. Generalized Born. Journal of Chemical Theory and Computation, 8(5), 1542-1555. doi:10.1021/ct200909jLe Grand, S., Götz, A. W., & Walker, R. C. (2013). SPFP: Speed without compromise—A mixed precision model for GPU accelerated molecular dynamics simulations. Computer Physics Communications, 184(2), 374-380. doi:10.1016/j.cpc.2012.09.022Darden, T., York, D., & Pedersen, L. (1993). Particle mesh Ewald: AnN⋅log(N) method for Ewald sums in large systems. The Journal of Chemical Physics, 98(12), 10089-10092. doi:10.1063/1.464397Ryckaert, J.-P., Ciccotti, G., & Berendsen, H. J. . (1977). Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. Journal of Computational Physics, 23(3), 327-341. doi:10.1016/0021-9991(77)90098-5W. L. DeLano , The PyMOL Molecular Graphics System , DeLano Scientific LLC , Palo Alto, CA, USA , 2008 . http://www.pymol.org/Roe, D. R., & Cheatham, T. E. (2013). PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data. Journal of Chemical Theory and Computation, 9(7), 3084-3095. doi:10.1021/ct400341phttp://www.amber.utah.edu/AMBER-workshop/London-2015/pca