A framework to predict the price of energy for the end-users with applications to monetary and energy policies.

Energy affects every single individual and entity in the world. Therefore, it is crucial to precisely quantify the "price of energy" and study how it evolves through time, through major political and social events, and through changes in energy and monetary policies. Here, we develop a predictive framework, an index to calculate the average price of energy in the United States. The complex energy landscape is thoroughly analysed to accurately determine the two key factors of this framework: the total demand of the energy products directed to the end-use sectors, and the corresponding price of each product. A rolling horizon predictive methodology is introduced to estimate future energy demands, with excellent predictive capability, shown over a period of 174 months. The effectiveness of the framework is demonstrated by addressing two policy questions of significant public interest.

Optimal Design of Energy Systems Using Constrained Grey-Box Multi-Objective Optimization.

The (global) optimization of energy systems, commonly characterized by high-fidelity and large-scale complex models, poses a formidable challenge partially due to the high noise and/or computational expense associated with the calculation of derivatives. This complexity is further amplified in the presence of multiple conflicting objectives, for which the goal is to generate trade-off compromise solutions, commonly known as Pareto-optimal solutions. We have previously introduced the p-ARGONAUT system, parallel AlgoRithms for Global Optimization of coNstrAined grey-box compUTational problems, which is designed to optimize general constrained single objective grey-box problems by postulating accurate and tractable surrogate formulations for all unknown equations in a computationally efficient manner. In this work, we extend p-ARGONAUT towards multi-objective optimization problems and test the performance of the framework, both in terms of accuracy and consistency, under many equality constraints. Computational results are reported for a number of benchmark multi-objective problems and a case study of an energy market design problem for a commercial building, while the performance of the framework is compared with other derivative-free optimization solvers.

Big Data Approach to Batch Process Monitoring: Simultaneous Fault Detection and Diagnosis Using Nonlinear Support Vector Machine-based Feature Selection.

This paper presents a novel data-driven framework for process monitoring in batch processes, a critical task in industry to attain a safe operability and minimize loss of productivity and profit. We exploit high dimensional process data with nonlinear Support Vector Machine-based feature selection algorithm, where we aim to retrieve the most informative process measurements for accurate and simultaneous fault detection and diagnosis. The proposed framework is applied to an extensive benchmark dataset which includes process data describing 22,200 batches with 15 faults. We train fault and time-specific models on the prealigned batch data trajectories via three distinct time horizon approaches: one-step rolling, two-step rolling, and evolving which varies the amount of data incorporation during modeling. The results show that two-step rolling and evolving time horizon approaches perform superior to the other. Regardless of the approach, proposed framework provides a promising decision support tool for online simultaneous fault detection and diagnosis for batch processes.

Princeton_TIGRESS 2.0: High refinement consistency and net gains through support vector machines and molecular dynamics in double-blind predictions during the CASP11 experiment.

Protein structure refinement is the challenging problem of operating on any protein structure prediction to improve its accuracy with respect to the native structure in a blind fashion. Although many approaches have been developed and tested during the last four CASP experiments, a majority of the methods continue to degrade models rather than improve them. Princeton_TIGRESS (Khoury et al., Proteins 2014;82:794-814) was developed previously and utilizes separate sampling and selection stages involving Monte Carlo and molecular dynamics simulations and classification using an SVM predictor. The initial implementation was shown to consistently refine protein structures 76% of the time in our own internal benchmarking on CASP 7-10 targets. In this work, we improved the sampling and selection stages and tested the method in blind predictions during CASP11. We added a decomposition of physics-based and hybrid energy functions, as well as a coordinate-free representation of the protein structure through distance-binning Cα-Cα distances to capture fine-grained movements. We performed parameter estimation to optimize the adjustable SVM parameters to maximize precision while balancing sensitivity and specificity across all cross-validated data sets, finding enrichment in our ability to select models from the populations of similar decoys generated for targets in CASPs 7-10. The MD stage was enhanced such that larger structures could be further refined. Among refinement methods that are currently implemented as web-servers, Princeton_TIGRESS 2.0 demonstrated the most consistent and most substantial net refinement in blind predictions during CASP11. The enhanced refinement protocol Princeton_TIGRESS 2.0 is freely available as a web server at http://atlas.engr.tamu.edu/refinement/. Proteins 2017; 85:1078-1098. © 2017 Wiley Periodicals, Inc.

Discovery of functionally selective C5aR2 ligands: novel modulators of C5a signalling.

The complement cascade is comprised of a highly sophisticated network of innate immune proteins that are activated in response to invading pathogens or tissue injury. The complement activation peptide, C5a, binds two seven transmembrane receptors, namely the C5a receptor 1 (C5aR1) and C5a receptor 2 (C5aR2, or C5L2). C5aR2 is a non-G-protein-signalling receptor whose biological role remains controversial. Some of this controversy arises owing to the lack of selective ligands for C5aR2. In this study, a library of 61 peptides based on the C-terminus of C5a was assayed for the ability to selectively modulate C5aR2 function. Two ligands (P32 and P59) were identified as functionally selective C5aR2 ligands, exhibiting selective recruitment of ß-arrestin 2 via C5aR2, partial inhibition of C5a-induced ERK1/2 activation and lipopolysaccharide-stimulated interleukin-6 release from human monocyte-derived macrophages. Importantly, neither ligand could induce ERK1/2 activation or inhibit C5a-induced ERK1/2 activation via C5aR1 directly. Finally, P32 inhibited C5a-mediated neutrophil mobilisation in wild-type, but not C5aR2(-/-) mice. These functionally selective ligands for C5aR2 are novel tools that can selectively modulate C5a activity in vitro and in vivo, and thus will be valuable tools to interrogate C5aR2 function.

conSSert: Consensus SVM Model for Accurate Prediction of Ordered Secondary Structure.

Accurate prediction of protein secondary structure remains a crucial step in most approaches to the protein-folding problem, yet the prediction of ordered secondary structure, specifically beta-strands, remains a challenge. We developed a consensus secondary structure prediction method, conSSert, which is based on support vector machines (SVM) and provides exceptional accuracy for the prediction of beta-strands with QE accuracy of over 0.82 and a Q2-EH of 0.86. conSSert uses as input probabilities for the three types of secondary structure (helix, strand, and coil) that are predicted by four top performing methods: PSSpred, PSIPRED, SPINE-X, and RAPTOR. conSSert was trained/tested using 4261 protein chains from PDBSelect25, and 8632 chains from PISCES. Further validation was performed using targets from CASP9, CASP10, and CASP11. Our data suggest that poor performance in strand prediction is likely a result of training bias and not solely due to the nonlocal nature of beta-sheet contacts. conSSert is freely available for noncommercial use as a webservice: http://ares.tamu.edu/conSSert/.

Highly Accurate Structure-Based Prediction of HIV-1 Coreceptor Usage Suggests Intermolecular Interactions Driving Tropism.

HIV-1 entry into host cells is mediated by interactions between the V3-loop of viral glycoprotein gp120 and chemokine receptor CCR5 or CXCR4, collectively known as HIV-1 coreceptors. Accurate genotypic prediction of coreceptor usage is of significant clinical interest and determination of the factors driving tropism has been the focus of extensive study. We have developed a method based on nonlinear support vector machines to elucidate the interacting residue pairs driving coreceptor usage and provide highly accurate coreceptor usage predictions. Our models utilize centroid-centroid interaction energies from computationally derived structures of the V3-loop:coreceptor complexes as primary features, while additional features based on established rules regarding V3-loop sequences are also investigated. We tested our method on 2455 V3-loop sequences of various lengths and subtypes, and produce a median area under the receiver operator curve of 0.977 based on 500 runs of 10-fold cross validation. Our study is the first to elucidate a small set of specific interacting residue pairs between the V3-loop and coreceptors capable of predicting coreceptor usage with high accuracy across major HIV-1 subtypes. The developed method has been implemented as a web tool named CRUSH, CoReceptor USage prediction for HIV-1, which is available at http://ares.tamu.edu/CRUSH/.

COMSAT: Residue contact prediction of transmembrane proteins based on support vector machines and mixed integer linear programming.

In this article, we present COMSAT, a hybrid framework for residue contact prediction of transmembrane (TM) proteins, integrating a support vector machine (SVM) method and a mixed integer linear programming (MILP) method. COMSAT consists of two modules: COMSAT_SVM which is trained mainly on position-specific scoring matrix features, and COMSAT_MILP which is an ab initio method based on optimization models. Contacts predicted by the SVM model are ranked by SVM confidence scores, and a threshold is trained to improve the reliability of the predicted contacts. For TM proteins with no contacts above the threshold, COMSAT_MILP is used. The proposed hybrid contact prediction scheme was tested on two independent TM protein sets based on the contact definition of 14 Å between Cα-Cα atoms. First, using a rigorous leave-one-protein-out cross validation on the training set of 90 TM proteins, an accuracy of 66.8%, a coverage of 12.3%, a specificity of 99.3% and a Matthews' correlation coefficient (MCC) of 0.184 were obtained for residue pairs that are at least six amino acids apart. Second, when tested on a test set of 87 TM proteins, the proposed method showed a prediction accuracy of 64.5%, a coverage of 5.3%, a specificity of 99.4% and a MCC of 0.106. COMSAT shows satisfactory results when compared with 12 other state-of-the-art predictors, and is more robust in terms of prediction accuracy as the length and complexity of TM protein increase. COMSAT is freely accessible at http://hpcc.siat.ac.cn/COMSAT/.

New compstatin peptides containing N-terminal extensions and non-natural amino acids exhibit potent complement inhibition and improved solubility characteristics.

Compstatin peptides are complement inhibitors that bind and inhibit cleavage of complement C3. Peptide binding is enhanced by hydrophobic interactions; however, poor solubility promotes aggregation in aqueous environments. We have designed new compstatin peptides derived from the W4A9 sequence (Ac-ICVWQDWGAHRCT-NH2, cyclized between C2 and C12), based on structural, computational, and experimental studies. Furthermore, we developed and utilized a computational framework for the design of peptides containing non-natural amino acids. These new compstatin peptides contain polar N-terminal extensions and non-natural amino acid substitutions at positions 4 and 9. Peptides with α-modified non-natural alanine analogs at position 9, as well as peptides containing only N-terminal polar extensions, exhibited similar activity compared to W4A9, as quantified via ELISA, hemolytic, and cell-based assays, and showed improved solubility, as measured by UV absorbance and reverse-phase HPLC experiments. Because of their potency and solubility, these peptides are promising candidates for therapeutic development in numerous complement-mediated diseases.

Derivation of ligands for the complement C3a receptor from the C-terminus of C5a.

The complement cascade is a highly sophisticated network of proteins that are well regulated and directed in response to invading pathogens or tissue injury. Complement C3a and C5a are key mediators produced by this cascade, and their dysregulation has been linked to a plethora of inflammatory and autoimmune diseases. Consequently, this has stimulated interest in the development of ligands for the receptors for these complement peptides, C3a receptor, and C5a1 (C5aR/CD88). In this study we used computational methods to design novel C5a1 receptor ligands. However, functional screening in human monocyte-derived macrophages using the xCELLigence label-free platform demonstrated altered specificity of our ligands. No agonist/antagonist activity was observed at C5a1, but we instead saw that the ligands were able to partially agonize the closely related complement receptor C3a receptor. This was verified in the presence of C3a receptor antagonist SB 290157 and in a stable cell line expressing either C5a1 or C3a receptor alone. C3a agonism has been suggested to be a potential treatment of acute neutrophil-driven traumatic pathologies, and may have great potential as a therapeutic avenue in this arena.

De novo design and experimental characterization of ultrashort self-associating peptides.

Self-association is a common phenomenon in biology and one that can have positive and negative impacts, from the construction of the architectural cytoskeleton of cells to the formation of fibrils in amyloid diseases. Understanding the nature and mechanisms of self-association is important for modulating these systems and in creating biologically-inspired materials. Here, we present a two-stage de novo peptide design framework that can generate novel self-associating peptide systems. The first stage uses a simulated multimeric template structure as input into the optimization-based Sequence Selection to generate low potential energy sequences. The second stage is a computational validation procedure that calculates Fold Specificity and/or Approximate Association Affinity (K*association) based on metrics that we have devised for multimeric systems. This framework was applied to the design of self-associating tripeptides using the known self-associating tripeptide, Ac-IVD, as a structural template. Six computationally predicted tripeptides (Ac-LVE, Ac-YYD, Ac-LLE, Ac-YLD, Ac-MYD, Ac-VIE) were chosen for experimental validation in order to illustrate the self-association outcomes predicted by the three metrics. Self-association and electron microscopy studies revealed that Ac-LLE formed bead-like microstructures, Ac-LVE and Ac-YYD formed fibrillar aggregates, Ac-VIE and Ac-MYD formed hydrogels, and Ac-YLD crystallized under ambient conditions. An X-ray crystallographic study was carried out on a single crystal of Ac-YLD, which revealed that each molecule adopts a ß-strand conformation that stack together to form parallel ß-sheets. As an additional validation of the approach, the hydrogel-forming sequences of Ac-MYD and Ac-VIE were shuffled. The shuffled sequences were computationally predicted to have lower K*association values and were experimentally verified to not form hydrogels. This illustrates the robustness of the framework in predicting self-associating tripeptides. We expect that this enhanced multimeric de novo peptide design framework will find future application in creating novel self-associating peptides based on unnatural amino acids, and inhibitor peptides of detrimental self-aggregating biological proteins.

Elucidating a key anti-HIV-1 and cancer-associated axis: the structure of CCL5 (Rantes) in complex with CCR5.

CCL5 (RANTES) is an inflammatory chemokine which binds to chemokine receptor CCR5 and induces signaling. The CCL5:CCR5 associated chemotactic signaling is of critical biological importance and is a potential HIV-1 therapeutic axis. Several studies provided growing evidence for the expression of CCL5 and CCR5 in non-hematological malignancies. Therefore, the delineation of the CCL5:CCR5 complex structure can pave the way for novel CCR5-targeted drugs. We employed a computational protocol which is primarily based on free energy calculations and molecular dynamics simulations, and report, what is to our knowledge, the first computationally derived CCL5:CCR5 complex structure which is in excellent agreement with experimental findings and clarifies the functional role of CCL5 and CCR5 residues which are associated with binding and signaling. A wealth of polar and non-polar interactions contributes to the tight CCL5:CCR5 binding. The structure of an HIV-1 gp120 V3 loop in complex with CCR5 has recently been derived through a similar computational protocol. A comparison between the CCL5 : CCR5 and the HIV-1 gp120 V3 loop : CCR5 complex structures depicts that both the chemokine and the virus primarily interact with the same CCR5 residues. The present work provides insights into the blocking mechanism of HIV-1 by CCL5.

Forcefield_NCAA: ab initio charge parameters to aid in the discovery and design of therapeutic proteins and peptides with unnatural amino acids and their application to complement inhibitors of the compstatin family.

We describe the development and testing of ab initio derived, AMBER ff03 compatible charge parameters for a large library of 147 noncanonical amino acids including ß- and N-methylated amino acids for use in applications such as protein structure prediction and de novo protein design. The charge parameter derivation was performed using the RESP fitting approach. Studies were performed assessing the suitability of the derived charge parameters in discriminating the activity/inactivity between 63 analogs of the complement inhibitor Compstatin on the basis of previously published experimental IC50 data and a screening procedure involving short simulations and binding free energy calculations. We found that both the approximate binding affinity (K*) and the binding free energy calculated through MM-GBSA are capable of discriminating between active and inactive Compstatin analogs, with MM-GBSA performing significantly better. Key interactions between the most potent Compstatin analog that contains a noncanonical amino acid are presented and compared to the most potent analog containing only natural amino acids and native Compstatin. We make the derived parameters and an associated web interface that is capable of performing modifications on proteins using Forcefield_NCAA and outputting AMBER-ready topology and parameter files freely available for academic use at http://selene.princeton.edu/FFNCAA . The forcefield allows one to incorporate these customized amino acids into design applications with control over size, van der Waals, and electrostatic interactions.

Molecular recognition of CCR5 by an HIV-1 gp120 V3 loop.

The binding of protein HIV-1 gp120 to coreceptors CCR5 or CXCR4 is a key step of the HIV-1 entry to the host cell, and is predominantly mediated through the V3 loop fragment of HIV-1 gp120. In the present work, we delineate the molecular recognition of chemokine receptor CCR5 by a dual tropic HIV-1 gp120 V3 loop, using a comprehensive set of computational tools predominantly based on molecular dynamics simulations and free energy calculations. We report, what is to our knowledge, the first complete HIV-1 gp120 V3 loop : CCR5 complex structure, which includes the whole V3 loop and the N-terminus of CCR5, and exhibits exceptional agreement with previous experimental findings. The computationally derived structure sheds light into the functional role of HIV-1 gp120 V3 loop and CCR5 residues associated with the HIV-1 coreceptor activity, and provides insights into the HIV-1 coreceptor selectivity and the blocking mechanism of HIV-1 gp120 by maraviroc. By comparing the binding of the specific dual tropic HIV-1 gp120 V3 loop with CCR5 and CXCR4, we observe that the HIV-1 gp120 V3 loop residues 13-21, which include the tip, share nearly identical structural and energetic properties in complex with both coreceptors. This result paves the way for the design of dual CCR5/CXCR4 targeted peptides as novel potential anti-AIDS therapeutics.

De novo peptide design and experimental validation of histone methyltransferase inhibitors.

Histones are small proteins critical to the efficient packaging of DNA in the nucleus. DNA­protein complexes, known as nucleosomes, are formed when the DNA winds itself around the surface of the histones. The methylation of histone residues by enhancer of zeste homolog 2 (EZH2) maintains gene repression over successive cell generations. Overexpression of EZH2 can silence important tumor suppressor genes leading to increased invasiveness of many types of cancers. This makes the inhibition of EZH2 an important target in the development of cancer therapeutics. We employed a three-stage computational de novo peptide design method to design inhibitory peptides of EZH2. The method consists of a sequence selection stage and two validation stages for fold specificity and approximate binding affinity. The sequence selection stage consists of an integer linear optimization model that was solved to produce a rank-ordered list of amino acid sequences with increased stability in the bound peptide-EZH2 structure. These sequences were validated through the calculation of the fold specificity and approximate binding affinity of the designed peptides. Here we report the discovery of novel EZH2 inhibitory peptides using the de novo peptide design method. The computationally discovered peptides were experimentally validated in vitro using dose titrations and mechanism of action enzymatic assays. The peptide with the highest in vitro response, SQ037, was validated in nucleo using quantitative mass spectrometry-based proteomics. This peptide had an IC50 of 13.5 mM, demonstrated greater potency as an inhibitor when compared to the native and K27A mutant control peptides, and demonstrated competitive inhibition versus the peptide substrate. Additionally, this peptide demonstrated high specificity to the EZH2 target in comparison to other histone methyltransferases. The validated peptides are the first computationally designed peptides that directly inhibit EZH2. These inhibitors should prove useful for further chromatin biology investigations.

De novo peptide design and experimental validation of histone methyltransferase inhibitors.

Histones are small proteins critical to the efficient packaging of DNA in the nucleus. DNA-protein complexes, known as nucleosomes, are formed when the DNA winds itself around the surface of the histones. The methylation of histone residues by enhancer of zeste homolog 2 (EZH2) maintains gene repression over successive cell generations. Overexpression of EZH2 can silence important tumor suppressor genes leading to increased invasiveness of many types of cancers. This makes the inhibition of EZH2 an important target in the development of cancer therapeutics. We employed a three-stage computational de novo peptide design method to design inhibitory peptides of EZH2. The method consists of a sequence selection stage and two validation stages for fold specificity and approximate binding affinity. The sequence selection stage consists of an integer linear optimization model that was solved to produce a rank-ordered list of amino acid sequences with increased stability in the bound peptide-EZH2 structure. These sequences were validated through the calculation of the fold specificity and approximate binding affinity of the designed peptides. Here we report the discovery of novel EZH2 inhibitory peptides using the de novo peptide design method. The computationally discovered peptides were experimentally validated in vitro using dose titrations and mechanism of action enzymatic assays. The peptide with the highest in vitro response, SQ037, was validated in nucleo using quantitative mass spectrometry-based proteomics. This peptide had an IC50 of 13.5 [Formula: see text]M, demonstrated greater potency as an inhibitor when compared to the native and K27A mutant control peptides, and demonstrated competitive inhibition versus the peptide substrate. Additionally, this peptide demonstrated high specificity to the EZH2 target in comparison to other histone methyltransferases. The validated peptides are the first computationally designed peptides that directly inhibit EZH2. These inhibitors should prove useful for further chromatin biology investigations.

Energy supply chain optimization of hybrid feedstock processes: a review.

The economic, environmental, and social performances of energy systems depend on their geographical locations and the surrounding market infrastructure for feedstocks and energy products. Strategic decisions to locate energy conversion facilities must take all upstream and downstream operations into account, prompting the development of supply chain modeling and optimization methods. This article reviews the contributions of energy supply chain studies that include heat, power, and liquid fuels production. Studies are categorized based on specific features of the mathematical model, highlighting those that address energy supply chain models with and without considerations of multiperiod decisions. Studies that incorporate uncertainties are discussed, and opportunities for future research developments are outlined.

Elucidating a key component of cancer metastasis: CXCL12 (SDF-1α) binding to CXCR4.

The chemotactic signaling induced by the binding of chemokine CXCL12 (SDF-1α) to chemokine receptor CXCR4 is of significant biological importance and is a potential therapeutic axis against HIV-1. However, as CXCR4 is overexpressed in certain cancer cells, the CXCL12:CXCR4 signaling is involved in tumor metastasis, progression, angiogenesis, and survival. Motivated by the pivotal role of the CXCL12:CXCR4 axis in cancer, we employed a comprehensive set of computational tools, predominantly based on free energy calculations and molecular dynamics simulations, to obtain insights into the molecular recognition of CXCR4 by CXCL12. We report, what is to our knowledge, the first computationally derived CXCL12:CXCR4 complex structure which is in remarkable agreement with experimental findings and sheds light into the functional role of CXCL12 and CXCR4 residues which are associated with binding and signaling. Our results reveal that the CXCL12 N-terminal domain is firmly bound within the CXCR4 transmembrane domain, and the central 24-50 residue domain of CXCL12 interacts with the upper N-terminal domain of CXCR4. The stability of the CXCL12:CXCR4 complex structure is attributed to an abundance of nonpolar and polar intermolecular interactions, including salt bridges formed between positively charged CXCL12 residues and negatively charged CXCR4 residues. The success of the computational protocol can mainly be attributed to the nearly exhaustive docking conformational search, as well as the heterogeneous dielectric implicit water-membrane-water model used to simulate and select the optimum conformations. We also recently utilized this protocol to elucidate the binding of an HIV-1 gp120 V3 loop in complex with CXCR4, and a comparison between the molecular recognition of CXCR4 by CXCL12 and the HIV-1 gp120 V3 loop shows that both CXCL12 and the HIV-1 gp120 V3 loop share the same CXCR4 binding pocket, as they mostly interact with the same CXCR4 residues.

WeFold: a coopetition for protein structure prediction.

The protein structure prediction problem continues to elude scientists. Despite the introduction of many methods, only modest gains were made over the last decade for certain classes of prediction targets. To address this challenge, a social-media based worldwide collaborative effort, named WeFold, was undertaken by 13 labs. During the collaboration, the laboratories were simultaneously competing with each other. Here, we present the first attempt at "coopetition" in scientific research applied to the protein structure prediction and refinement problems. The coopetition was possible by allowing the participating labs to contribute different components of their protein structure prediction pipelines and create new hybrid pipelines that they tested during CASP10. This manuscript describes both successes and areas needing improvement as identified throughout the first WeFold experiment and discusses the efforts that are underway to advance this initiative. A footprint of all contributions and structures are publicly accessible at http://www.wefold.org.

Proteomics for the discovery of biomarkers and diagnosis of periodontitis: a critical review.

Periodontitis is a common chronic and destructive disease whose pathogenetic mechanisms remain unclear. Due to their sensitivity and global scale, proteomics studies offer the opportunity to uncover critical host and pathogen activity indicators and can elucidate clinically applicable biomarkers for improved diagnosis and treatment of the disease. This review summarizes the literature of proteomics studies on periodontitis and comprehensively discusses commonly found candidate biomarkers. Key considerations in the design of an experimental proteomics platform are also outlined. The applicability of protein biomarkers across the progression of periodontitis and unexplored areas of research are highlighted.