Browsing by Author "Wallqvist, Anders"
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- ItemAssessing deep and shallow learning methods for quantitative prediction of acute chemical toxicity.(0000-00-00) Liu, Ruifeng; Madore, Michael; Glover, Kyle P; Feasel, Michael G; Wallqvist, AndersAnimal based methods for assessing chemical toxicity are struggling to meet testing demands In silico approaches including machine learning methods are promising alternatives Recently deep neural networks DNNs were evaluated and reported to outperform other machine learning methods for quantitative structure activity relationship modeling of molecular properties However most of the reported performance evaluations relied on global performance metrics such as the root mean squared error RMSE between the predicted and experimental values of all samples without considering the impact of sample distribution across the activity spectrum Here we carried out an in depth analysis of DNN performance for quantitative prediction of acute chemical toxicity using several datasets We found that the overall performance of DNN models on datasets of up to 30 000 compounds was similar to that of random forest RF models as measured by the RMSE and correlation coefficients between the predicted and experimental results However our detailed analyses demonstrated that global performance metrics are inappropriate for datasets with a highly uneven sample distribution because they show a strong bias for the most populous compounds along the toxicity spectrum For highly toxic compounds DNN and RF models trained on all samples performed much worse than the global performance metrics indicated Surprisingly our variable nearest neighbor method which utilizes only structurally similar compounds to make predictions performed reasonably well suggesting that information of close near neighbors in the training sets is a key determinant of acute toxicity predictions
- ItemCan computationally designed protein sequences improve secondary structure prediction?(2011-04-18) Bondugula, Rajkumar; Wallqvist, Anders; Lee, Michael SComputational sequence design methods are used to engineer proteins with desired properties such as increased thermal stability and novel function In addition these algorithms can be used to identify an envelope of sequences that may be compatible with a particular protein fold topology In this regard we hypothesized that sequence property prediction specifically secondary structure could be significantly enhanced by using a large database of computationally designed sequences We performed a large scale test of this hypothesis with 6511 diverse protein domains and 50 designed sequences per domain After analysis of the inherent accuracy of the designed sequences database we realized that it was necessary to put constraints on what fraction of the native sequence should be allowed to change With mutational constraints accuracy was improved vs no constraints but the diversity of designed sequences and hence effective size of the database was moderately reduced Overall the best three state prediction accuracy Q 3 that we achieved was nearly a percentage point improved over using a natural sequence database alone well below the theoretical possibility for improvement of 8 10 percentage points Furthermore our nascent method was used to augment the state of the art PSIPRED program by a percentage point
- ItemCharacterization of chemically induced liver injuries using gene co-expression modules.(2014-09-17) Tawa, Gregory J; AbdulHameed, Mohamed Diwan M; Yu, Xueping; Kumar, Kamal; Ippolito, Danielle L; Lewis, John A; Stallings, Jonathan D; Wallqvist, AndersLiver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non invasive diagnostic tests Mapping chemical injuries to organ specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests Here we have used DrugMatrix a toxicogenomics database containing organ specific gene expression data matched to dose dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats to identify groups of co expressed genes modules specific to injury endpoints in the liver We identified 78 such gene co expression modules associated with 25 diverse injury endpoints categorized from clinical pathology organ weight changes and histopathology Using gene expression data associated with an injury condition we showed that these modules exhibited different patterns of activation characteristic of each injury We further showed that specific module genes mapped to 1 known biochemical pathways associated with liver injuries and 2 clinically used diagnostic tests for liver fibrosis As such the gene modules have characteristics of both generalized and specific toxic response pathways Using these results we proposed three gene signature sets characteristic of liver fibrosis steatosis and general liver injury based on genes from the co expression modules Out of all 92 identified genes 18 20 genes have well documented relationships with liver disease whereas the rest are novel and have not previously been associated with liver disease In conclusion identifying gene co expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects
- ItemComputational approach to characterize causative factors and molecular indicators of chronic wound inflammation.(2014-02-10) Nagaraja, Sridevi; Wallqvist, Anders; Reifman, Jaques; Mitrophanov, Alexander YChronic inflammation is rapidly becoming recognized as a key contributor to numerous pathologies Despite detailed investigations understanding of the molecular mechanisms regulating inflammation is incomplete Knowledge of such critical regulatory processes and informative indicators of chronic inflammation is necessary for efficacious therapeutic interventions and diagnostic support to clinicians We used a computational modeling approach to elucidate the critical factors responsible for chronic inflammation and to identify robust molecular indicators of chronic inflammatory conditions Our kinetic model successfully captured experimentally observed cell and cytokine dynamics for both acute and chronic inflammatory responses Using sensitivity analysis we identified macrophage influx and efflux rate modulation as the strongest inducing factor of chronic inflammation for a wide range of scenarios Moreover our model predicted that among all major inflammatory mediators IL 6 TGF and PDGF may generally be considered the most sensitive and robust indicators of chronic inflammation which is supported by existing but limited experimental evidence
- ItemA computational study of the respiratory airflow characteristics in normal and obstructed human airways.(2014-08-18) Sul, Bora; Wallqvist, Anders; Morris, Michael J; Reifman, Jaques; Rakesh, VineetObstructive lung diseases in the lower airways are a leading health concern worldwide To improve our understanding of the pathophysiology of lower airways we studied airflow characteristics in the lung between the 8th and the 14th generations using a three dimensional computational fluid dynamics model where we compared normal and obstructed airways for a range of breathing conditions We employed a novel technique based on computing the Pearson s correlation coefficient to quantitatively characterize the differences in airflow patterns between the normal and obstructed airways We found that the airflow patterns demonstrated clear differences between normal and diseased conditions for high expiratory flow rates 2300ml s but not for inspiratory flow rates Moreover airflow patterns subjected to filtering demonstrated higher sensitivity than airway resistance for differentiating normal and diseased conditions Further we showed that wall shear stresses were not only dependent on breathing rates but also on the distribution of the obstructed sites in the lung for the same degree of obstruction and breathing rate we observed as much as two fold differences in shear stresses In contrast to previous studies that suggest increased wall shear stress due to obstructions as a possible damage mechanism for small airways our model demonstrated that for flow rates corresponding to heavy activities the wall shear stress in both normal and obstructed airways was Under0 3Pa which is within the physiological limit needed to promote respiratory defense mechanisms In summary our model enables the study of airflow characteristics that may be impractical to assess experimentally
- ItemComputing Relative Free Energies of Solvation using Single Reference Thermodynamic Integration Augmented with Hamiltonian Replica Exchange.(2010-12-14) Khavrutskii, Ilja V; Wallqvist, AndersThis paper introduces an efficient single topology variant of Thermodynamic Integration TI for computing relative transformation free energies in a series of molecules with respect to a single reference state The presented TI variant that we refer to as Single Reference TI SR TI combines well established molecular simulation methodologies into a practical computational tool Augmented with Hamiltonian Replica Exchange HREX the SR TI variant can deliver enhanced sampling in select degrees of freedom The utility of the SR TI variant is demonstrated in calculations of relative solvation free energies for a series of benzene derivatives with increasing complexity Noteworthy the SR TI variant with the HREX option provides converged results in a challenging case of an amide molecule with a high 13 15 kcal mol barrier for internal cis trans interconversion using simulation times of only 1 to 4 ns
- ItemDBSecSys: a database of Burkholderia mallei secretion systems.(2014-07-25) Memišević, Vesna; Kumar, Kamal; Cheng, Li; Zavaljevski, Nela; DeShazer, David; Wallqvist, Anders; Reifman, JaquesBacterial pathogenicity represents a major public health concern worldwide Secretion systems are a key component of bacterial pathogenicity as they provide the means for bacterial proteins to penetrate host cell membranes and insert themselves directly into the host cells cytosol Burkholderia mallei is a Gram negative bacterium that uses multiple secretion systems during its host infection life cycle To date the identities of secretion system proteins for B mallei are not well known and their pathogenic mechanisms of action and host factors are largely uncharacterized
- ItemDOVIS: an implementation for high-throughput virtual screening using AutoDock.(2008-03-27) Zhang, Shuxing; Kumar, Kamal; Jiang, Xiaohui; Wallqvist, Anders; Reifman, JaquesMolecular docking based virtual screening is an important tool in drug discovery that is used to significantly reduce the number of possible chemical compounds to be investigated In addition to the selection of a sound docking strategy with appropriate scoring functions another technical challenge is to in silico screen millions of compounds in a reasonable time To meet this challenge it is necessary to use high performance computing HPC platforms and techniques However the development of an integrated HPC system that makes efficient use of its elements is not trivial
- ItemEvidence of probabilistic behaviour in protein interaction networks.(2008-03-27) Ivanic, Joseph; Wallqvist, Anders; Reifman, JaquesData from high throughput experiments of protein protein interactions are commonly used to probe the nature of biological organization and extract functional relationships between sets of proteins What has not been appreciated is that the underlying mechanisms involved in assembling these networks may exhibit considerable probabilistic behaviour
- ItemExploiting large-scale drug-protein interaction information for computational drug repurposing.(2014-07-03) Liu, Ruifeng; Singh, Narender; Tawa, Gregory J; Wallqvist, Anders; Reifman, JaquesDespite increased investment in pharmaceutical research and development fewer and fewer new drugs are entering the marketplace This has prompted studies in repurposing existing drugs for use against diseases with unmet medical needs A popular approach is to develop a classification model based on drugs with and without a desired therapeutic effect For this approach to be statistically sound it requires a large number of drugs in both classes However given few or no approved drugs for the diseases of highest medical urgency and interest different strategies need to be investigated
- ItemExploring chemical reaction mechanisms through harmonic Fourier beads path optimization.(2013-11-04) Khavrutskii, Ilja V; Smith, Jason B; Wallqvist, AndersHere we apply the harmonic Fourier beads HFB path optimization method to study chemical reactions involving covalent bond breaking and forming on quantum mechanical QM and hybrid QM molecular mechanical QM MM potential energy surfaces To improve efficiency of the path optimization on such computationally demanding potentials we combined HFB with conjugate gradient CG optimization The combined CG HFB method was used to study two biologically relevant reactions namely L to D alanine amino acid inversion and alcohol acylation by amides The optimized paths revealed several unexpected reaction steps in the gas phase For example on the B3LYP 6 31G d p potential we found that alanine inversion proceeded via previously unknown intermediates 2 iminopropane 1 1 diol and 3 amino 3 methyloxiran 2 ol The CG HFB method accurately located transition states aiding in the interpretation of complex reaction mechanisms Thus on the B3LYP 6 31G d p potential the gas phase activation barriers for the inversion and acylation reactions were 50 5 and 39 9 kcal mol respectively These barriers determine the spontaneous loss of amino acid chirality and cleavage of peptide bonds in proteins We conclude that the combined CG HFB method further advances QM and QM MM studies of reaction mechanisms
- ItemIdentification of the Toxicity Pathways Associated With Thioacetamide-Induced Injuries in Rat Liver and Kidney.(0000-00-00) Schyman, Patric; Printz, Richard L; Estes, Shanea K; Boyd, Kelli L; Shiota, Masakazu; Wallqvist, AndersIngestion or exposure to chemicals poses a serious health risk Early detection of cellular changes induced by such events is vital to identify appropriate countermeasures to prevent organ damage We hypothesize that chemically induced organ injuries are uniquely associated with a set module of genes exhibiting significant changes in expression We have previously identified gene modules specifically associated with organ injuries by analyzing gene expression levels in liver and kidney tissue from rats exposed to diverse chemical insults Here we assess and validate our injury associated gene modules by analyzing gene expression data in liver kidney and heart tissues obtained from Sprague Dawley rats exposed to thioacetamide a known liver toxicant that promotes fibrosis The rats were injected intraperitoneally with a low 25 mg kg or high 100 mg kg dose of thioacetamide for 8 or 24 h and definite organ injury was diagnosed by histopathology Injury associated gene modules indicated organ injury specificity with the liver being most affected by thioacetamide The most activated liver gene modules were those associated with inflammatory cell infiltration and fibrosis Previous studies on thioacetamide toxicity and our histological analyses supported these results signifying the potential of gene expression data to identify organ injuries
- ItemIdentifying cytochrome p450 functional networks and their allosteric regulatory elements.(2013-12-06) Liu, Jin; Tawa, Gregory J; Wallqvist, AndersCytochrome P450 CYP enzymes play key roles in drug metabolism and adverse drug drug interactions Despite tremendous efforts in the past decades essential questions regarding the function and activity of CYPs remain unanswered Here we used a combination of sequence based co evolutionary analysis and structure based anisotropic thermal diffusion ATD molecular dynamics simulations to detect allosteric networks of amino acid residues and characterize their biological and molecular functions We investigated four CYP subfamilies CYP1A CYP2D CYP2C and CYP3A that are involved in 90 of all metabolic drug transformations and identified four amino acid interaction networks associated with specific CYP functionalities i e membrane binding heme binding catalytic activity and dimerization Interestingly we did not detect any co evolved substrate binding network suggesting that substrate recognition is specific for each subfamily Analysis of the membrane binding networks revealed that different CYP proteins adopt different membrane bound orientations consistent with the differing substrate preference for each isoform The catalytic networks were associated with conservation of catalytic function among CYP isoforms whereas the dimerization network was specific to different CYP isoforms We further applied low temperature ATD simulations to verify proposed allosteric sites associated with the heme binding network and their role in regulating metabolic fate Our approach allowed for a broad characterization of CYP properties such as membrane interactions catalytic mechanisms dimerization and linking these to groups of residues that can serve as allosteric regulators The presented combined co evolutionary analysis and ATD simulation approach is also generally applicable to other biological systems where allostery plays a role
- ItemMerging applicability domains for in silico assessment of chemical mutagenicity.(2014-03-24) Liu, Ruifeng; Wallqvist, AndersUsing a benchmark Ames mutagenicity data set we evaluated the performance of molecular fingerprints as descriptors for developing quantitative structure activity relationship QSAR models and defining applicability domains with two machine learning methods random forest RF and variable nearest neighbor v NN The two methods focus on complementary aspects of chemical mutagenicity and use different characteristics of the molecular fingerprints to achieve high levels of prediction accuracies Thus while RF flags mutagenic compounds using the presence or absence of small molecular fragments akin to structural alerts the v NN method uses molecular structural similarity as measured by fingerprint based Tanimoto distances between molecules We showed that the extended connectivity fingerprints could intuitively be used to define and quantify an applicability domain for either method The importance of using applicability domains in QSAR modeling cannot be understated compounds that are outside the applicability domain do not have any close representative in the training set and therefore we cannot make reliable predictions Using either approach we developed highly robust models that rival the performance of a state of the art proprietary software package Importantly based on the complementary approach used by the methods we showed that by combining the model predictions we raised the applicability domain from roughly 80 to 90 These results indicated that the proposed QSAR protocol constituted a highly robust chemical mutagenicity prediction model
- ItemMetabolic network-based predictions of toxicant-induced metabolite changes in the laboratory rat.(0000-00-00) Pannala, Venkat R; Wall, Martha L; Estes, Shanea K; Trenary, Irina; O'Brien, Tracy P; Printz, Richard L; Vinnakota, Kalyan C; Reifman, Jaques; Shiota, Masakazu; Young, Jamey D; Wallqvist, AndersIn order to provide timely treatment for organ damage initiated by therapeutic drugs or exposure to environmental toxicants we first need to identify markers that provide an early diagnosis of potential adverse effects before permanent damage occurs Specifically the liver as a primary organ prone to toxicants induced injuries lacks diagnostic markers that are specific and sensitive to the early onset of injury Here to identify plasma metabolites as markers of early toxicant induced injury we used a constraint based modeling approach with a genome scale network reconstruction of rat liver metabolism to incorporate perturbations of gene expression induced by acetaminophen a known hepatotoxicant A comparison of the model results against the global metabolic profiling data revealed that our approach satisfactorily predicted altered plasma metabolite levels as early as 5 h after exposure to 2 g kg of acetaminophen and that 10 h after treatment the predictions significantly improved when we integrated measured central carbon fluxes Our approach is solely driven by gene expression and physiological boundary conditions and does not rely on any toxicant specific model component As such it provides a mechanistic model that serves as a first step in identifying a list of putative plasma metabolites that could change due to toxicant induced perturbations
- ItemModeling metabolism and stage-specific growth of Plasmodium falciparum HB3 during the intraerythrocytic developmental cycle.(2014-08-27) Fang, Xin; Reifman, Jaques; Wallqvist, AndersThe human malaria parasite Plasmodium falciparum goes through a complex life cycle including a roughly 48 hour long intraerythrocytic developmental cycle IDC in human red blood cells A better understanding of the metabolic processes required during the asexual blood stage reproduction will enhance our basic knowledge of P falciparum and help identify critical metabolic reactions and pathways associated with blood stage malaria We developed a metabolic network model that mechanistically links time dependent gene expression metabolism and stage specific growth allowing us to predict the metabolic fluxes the biomass production rates and the timing of production of the different biomass components during the IDC We predicted time and stage specific production of precursors and macromolecules for P falciparum strain HB3 allowing us to link specific metabolites to specific physiological functions For example we hypothesized that coenzyme A might be involved in late IDC DNA replication and cell division Moreover the predicted ATP metabolism indicated that energy was mainly produced from glycolysis and utilized for non metabolic processes Finally we used the model to classify the entire tricarboxylic acid cycle into segments each with a distinct function such as superoxide detoxification glutamate glutamine processing and metabolism of fumarate as a byproduct of purine biosynthesis By capturing the normal metabolic and growth progression in P falciparum during the IDC our model provides a starting point for further elucidation of strain specific metabolic activity host parasite interactions stress induced metabolic responses and metabolic responses to antimalarial drugs and drug candidates
- ItemNonequilibrium phase transitions associated with DNA replication.(2011-03-16) Woo, Hyung-June; Wallqvist, AndersThermodynamics governing the synthesis of DNA and RNA strands under a template is considered analytically and applied to the population dynamics of competing replicators We find a nonequilibrium phase transition for high values of polymerase fidelity in a single replicator where the two phases correspond to stationary states with higher elongation velocity and lower error rate than the other At the critical point the susceptibility linking velocity to thermodynamic force diverges The overall behavior closely resembles the liquid vapor phase transition in equilibrium For a population of self replicating macromolecules Eigen s error catastrophe transition precedes this thermodynamic phase transition during starvation For a given thermodynamic force the fitness of replicators increases with increasing polymerase fidelity above a threshold
- ItemOn the proper calculation of electrostatic interactions in solid-supported bilayer systems.(2011-02-09) Yeh, In-Chul; Wallqvist, AndersModeling systems that are not inherently isotropic e g extended bilayers using molecular simulation techniques poses a potential problem Since these methods rely on a finite number of atoms and molecules to describe the system periodic boundary conditions are implemented to avoid edge effects and capture long range electrostatic interactions Systems consisting of a solvated bilayer adsorbed on a solid surface and exposed to an air vacuum interface occur in many experimental settings and present some unique challenges in this respect Here we investigated the effects of implementing different electrostatic boundary conditions on the structural and electrostatic properties of a quartz water vacuum interface and a similar quartz supported hydrated lipid bilayer exposed to vacuum Since these interfacial systems have a net polarization implementing the standard Ewald summation with the conducting boundary condition for the electrostatic long range interactions introduced an artificial periodicity in the out of plane dimension In particular abnormal orientational polarizations of water were observed with the conducting boundary condition Implementing the Ewald summation technique with the planar vacuum boundary condition and calculating electrostatic properties compatible with the implemented electrostatic boundary condition removed these inconsistencies This formulation is generally applicable to similar interfacial systems in bulk solution
- ItemPrediction of metabolic flux distribution from gene expression data based on the flux minimization principle.(2014-11-15) Song, Hyun-Seob; Reifman, Jaques; Wallqvist, AndersPrediction of possible flux distributions in a metabolic network provides detailed phenotypic information that links metabolism to cellular physiology To estimate metabolic steady state fluxes the most common approach is to solve a set of macroscopic mass balance equations subjected to stoichiometric constraints while attempting to optimize an assumed optimal objective function This assumption is justifiable in specific cases but may be invalid when tested across different conditions cell populations or other organisms With an aim to providing a more consistent and reliable prediction of flux distributions over a wide range of conditions in this article we propose a framework that uses the flux minimization principle to predict active metabolic pathways from mRNA expression data The proposed algorithm minimizes a weighted sum of flux magnitudes while biomass production can be bounded to fit an ample range from very low to very high values according to the analyzed context We have formulated the flux weights as a function of the corresponding enzyme reaction s gene expression value enabling the creation of context specific fluxes based on a generic metabolic network In case studies of wild type Saccharomyces cerevisiae and wild type and mutant Escherichia coli strains our method achieved high prediction accuracy as gauged by correlation coefficients and sums of squared error with respect to the experimentally measured values In contrast to other approaches our method was able to provide quantitative predictions for both model organisms under a variety of conditions Our approach requires no prior knowledge or assumption of a context specific metabolic functionality and does not require trial and error parameter adjustments Thus our framework is of general applicability for modeling the transcription dependent metabolism of bacteria and yeasts
- ItemA reaction path study of the catalysis and inhibition of the Bacillus anthracis CapD γ-glutamyl transpeptidase.(2014-11-11) Khavrutskii, Ilja V; Legler, Patricia M; Friedlander, Arthur M; Wallqvist, AndersThe CapD enzyme of Bacillus anthracis is a glutamyl transpeptidase from the N terminal nucleophile hydrolase superfamily that covalently anchors the poly D glutamic acid pDGA capsule to the peptidoglycan The capsule hinders phagocytosis of B anthracis by host cells and is essential for virulence The role CapD plays in capsule anchoring and remodeling makes the enzyme a promising target for anthrax medical countermeasures Although the structure of CapD is known and a covalent inhibitor capsidin has been identified the mechanisms of CapD catalysis and inhibition are poorly understood Here we used a computational approach to map out the reaction steps involved in CapD catalysis and inhibition We found that the rate limiting step of either CapD catalysis or inhibition was a concerted asynchronous formation of the tetrahedral intermediate with a barrier of 22 23 kcal mol However the mechanisms of these reactions differed for the two amides The formation of the tetrahedral intermediate with pDGA was substrate assisted with two proton transfers In contrast capsidin formed the tetrahedral intermediate in a conventional way with one proton transfer Interestingly capsidin coupled a conformational change in the catalytic residue of the tetrahedral intermediate to stretching of the scissile amide bond Furthermore capsidin took advantage of iminol amide tautomerism of its diacetamide moiety to convert the tetrahedral intermediate to the acetylated CapD As evidence of the promiscuous nature of CapD the enzyme cleaved the amide bond of capsidin by attacking it on the opposite side compared to pDGA