Reaction rebalancing: a novel approach to curating reaction databases.

PURPOSE: Reaction databases are a key resource for a wide variety of applications in computational chemistry and biochemistry, including Computer-aided Synthesis Planning (CASP) and the large-scale analysis of metabolic networks. The full potential of these resources can only be realized if datasets are accurate and complete. Missing co-reactants and co-products, i.e., unbalanced reactions, however, are the rule rather than the exception. The curation and correction of such incomplete entries is thus an urgent need. METHODS: The SynRBL framework addresses this issue with a dual-strategy: a rule-based method for non-carbon compounds, using atomic symbols and counts for prediction, alongside a Maximum Common Subgraph (MCS)-based technique for carbon compounds, aimed at aligning reactants and products to infer missing entities. RESULTS: The rule-based method exceeded 99% accuracy, while MCS-based accuracy varied from 81.19 to 99.33%, depending on reaction properties. Furthermore, an applicability domain and a machine learning scoring function were devised to quantify prediction confidence. The overall efficacy of this framework was delineated through its success rate and accuracy metrics, which spanned from 89.83 to 99.75% and 90.85 to 99.05%, respectively. CONCLUSION: The SynRBL framework offers a novel solution for recalibrating chemical reactions, significantly enhancing reaction completeness. With rigorous validation, it achieved groundbreaking accuracy in reaction rebalancing. This sets the stage for future improvement in particular of atom-atom mapping techniques as well as of downstream tasks such as automated synthesis planning. SCIENTIFIC CONTRIBUTION: SynRBL features a novel computational approach to correcting unbalanced entries in chemical reaction databases. By combining heuristic rules for inferring non-carbon compounds and common subgraph searches to address carbon unbalance, SynRBL successfully addresses most instances of this problem, which affects the majority of data in most large-scale resources. Compared to alternative solutions, SynRBL achieves a dramatic increase in both success rate and accurary, and provides the first freely available open source solution for this problem.

Toward the Reconciliation of Inconsistent Molecular Structures from Biochemical Databases.

Information on the structure of molecules, retrieved via biochemical databases, plays a pivotal role in various disciplines, including metabolomics, systems biology, and drug discovery. No such database can be complete and it is often necessary to incorporate data from several sources. However, the molecular structure for a given compound is not necessarily consistent between databases. This article presents StructRecon, a novel tool for resolving unique molecular structures from database identifiers. Currently, identifiers from BiGG, ChEBI, Escherichia coli Metabolome Database (ECMDB), MetaNetX, and PubChem are supported. StructRecon traverses the cross-links between entries in different databases to construct what we call identifier graphs. The goal of these graphs is to offer a more complete view of the total information available on a given compound across all the supported databases. To reconcile discrepancies met during the traversal of the databases, we develop an extensible model for molecular structure supporting multiple independent levels of detail, which allows standardization of the structure to be applied iteratively. In some cases, our standardization approach results in multiple candidate structures for a given compound, in which case a random walk-based algorithm is used to select the most likely structure among incompatible alternatives. As a case study, we applied StructRecon to the EColiCore2 model. We found at least one structure for 98.66% of its compounds, which is more than twice as many as possible when using the databases in more standard ways not considering the complex network of cross-database references captured by our identifier graphs. StructRecon is open-source and modular, which enables support for more databases in the future.

The role of prophylactic administration of CPAP in general surgical wards after open visceral surgery in reducing postoperative pneumonia-a retrospective cohort study.

BACKGROUND: Postoperative pneumonia is a main adverse event that causes increased postoperative morbidity and prolonged length of hospital stay leading to high postoperative mortality. Continuous positive airway pressure (CPAP) is a type of non-invasive ventilation for the delivery of a positive airway pressure during respiration. In this study, we evaluated the impact of postoperative prophylactic CPAP on prevention of pneumonia in patients after open visceral surgery. METHODS: In this observational cohort study, we compared the rates of postoperative pneumonia in patients who underwent open major visceral surgery from January 2018 till August 2020 in the study and control group. The study group had postoperative prophylactic sessions of CPAP for 15 min, 3-5 times a day and a repeated spirometer training was also performed in the general surgical ward. The control group received only the postoperative spirometer training as a prophylactic measure against postoperative pneumonia. The chi-square test was used to measure the relationships between categorical variables, and a binary regression analysis determined the correlation between independent and dependent variables. RESULTS: A total of 258 patients met the inclusion criteria who had open visceral surgery for various clinical illnesses. There were 146 men (56.6%) and 112 women with a mean age of 68.62 years. As many as 142 patients received prophylactic CPAP and they were grouped into the study group, whereas 116 patients without prophylactic CPAP were placed in the control group. Overall, the rate of postoperative pneumonia was significantly less in the study group (5.6% vs. 25.9% in the control group; p-value < 0.0001), which could be confirmed by the regression analysis (OR 0.118, CI 95% 0.047-0.295, p < 0.001). CONCLUSION: Postoperative intermittent CPAP after open visceral surgery can be performed in a general surgical ward. Our study showed a significant association with a low rate of postoperative pneumonia, especially in high-risk patients. This leads to a significantly shorter postoperative hospital stay especially in high-risk patients after upper gastrointestinal surgery. TRIAL REGISTRATION NUMBER: DRKS00028988, 04.05.2022, retrospectively registered.

Representing Catalytic Mechanisms with Rule Composition.

An "imaginary transition structure" overlays the molecular graphs of the educt and product sides of an elementary chemical reaction in a single graph to highlight the changes in bond structure. We generalize this idea to reactions with complex mechanisms in a formally rigorous approach based on composing arrow-pushing steps represented as graph-transformation rules to construct an overall composite rule and a derived transition structure. This transition structure retains information about transient bond changes that are invisible at the overall level and can be constructed automatically from an existing database of detailed enzymatic mechanisms. We use the construction to (i) illuminate the distribution of catalytic action across enzymes and substrates and (ii) to search in a large database for reactions of known or unknown mechanisms that are compatible with the mechanism captured by the constructed composite rule.

Generic Context-Aware Group Contributions.

Many properties of molecules vary systematically with changes in the structural formula and can thus be estimated from regression models defined on small structural building blocks, usually functional groups. Typically, such approaches are limited to a particular class of compounds and requires hand-curated lists of chemically plausible groups. This limits their use in particular in the context of generative approaches to explore large chemical spaces. Here we overcome this limitation by proposing a generic group contribution method that iteratively identifies significant regressors of increasing size. To this end, LASSO regression is used and the context-dependent contributions are "anchored" around a reference edge to reduce ambiguities and prevent overcounting due to multiple embeddings. We benchmark our approach, which is available as "Context AwaRe Group cOntribution" ( CARGO), on artificial data, typical applications from chemical thermodynamics. As we shall see, this method yields stable results with accuracies comparable to other regression techniques. As a by-product, we obtain interpretable additive contributions for individual chemical bonds and correction terms depending on local contexts.

Graph transformation for enzymatic mechanisms.

MOTIVATION: The design of enzymes is as challenging as it is consequential for making chemical synthesis in medical and industrial applications more efficient, cost-effective and environmentally friendly. While several aspects of this complex problem are computationally assisted, the drafting of catalytic mechanisms, i.e. the specification of the chemical steps-and hence intermediate states-that the enzyme is meant to implement, is largely left to human expertise. The ability to capture specific chemistries of multistep catalysis in a fashion that enables its computational construction and design is therefore highly desirable and would equally impact the elucidation of existing enzymatic reactions whose mechanisms are unknown. RESULTS: We use the mathematical framework of graph transformation to express the distinction between rules and reactions in chemistry. We derive about 1000 rules for amino acid side chain chemistry from the M-CSA database, a curated repository of enzymatic mechanisms. Using graph transformation, we are able to propose hundreds of hypothetical catalytic mechanisms for a large number of unrelated reactions in the Rhea database. We analyze these mechanisms to find that they combine in chemically sound fashion individual steps from a variety of known multistep mechanisms, showing that plausible novel mechanisms for catalysis can be constructed computationally. AVAILABILITY AND IMPLEMENTATION: The source code of the initial prototype of our approach is available at https://github.com/Nojgaard/mechsearch. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cayley Graphs of Semigroups Applied to Atom Tracking in Chemistry.

While atom tracking with isotope-labeled compounds is an essential and sophisticated wet-lab tool to, for example, illuminate reaction mechanisms, there exists only a limited amount of formal methods to approach the problem. Specifically, when large (bio-)chemical networks are considered where reactions are stereospecific, rigorous techniques are inevitable. We present an approach using the right Cayley graph of a monoid to track atoms concurrently through sequences of reactions and predict their potential location in product molecules. This can not only be used to systematically build hypothesis or reject reaction mechanisms (we will use the ANRORC mechanism "Addition of the Nucleophile, Ring Opening, and Ring Closure" as an example) but also to infer naturally occurring subsystems of (bio-)chemical systems. Our results include the analysis of the carbon traces within the tricarboxylic acid cycle and infer subsystems based on projections of the right Cayley graph onto a set of relevant atoms.

Combining Graph Transformations and Semigroups for Isotopic Labeling Design.

The double pushout approach for graph transformation naturally allows an abstraction level of biochemical systems in which individual atoms of molecules can be traced automatically within chemical reaction networks. Aiming at a mathematical rigorous approach for isotope labeling design, we convert chemical reaction networks (represented as directed hypergraphs) into transformation semigroups. Symmetries within molecules correspond to permutations, whereas (not necessarily invertible) chemical reactions define the transformations of the semigroup. An approach for the automatic inference of informative labeling of atoms is presented, which allows to distinguish the activity of different pathway alternatives within reaction networks. To illustrate our approaches, we apply them to the reaction network of glycolysis, which is an important and well-understood process that allows for different alternatives to convert glucose into pyruvate.

Chemical Transformation Motifs-Modelling Pathways as Integer Hyperflows.

We present an elaborate framework for formally modelling pathways in chemical reaction networks on a mechanistic level. Networks are modelled mathematically as directed multi-hypergraphs, with vertices corresponding to molecules and hyperedges to reactions. Pathways are modelled as integer hyperflows and we expand the network model by detailed routing constraints. In contrast to the more traditional approaches like Flux Balance Analysis or Elementary Mode analysis we insist on integer-valued flows. While this choice makes it necessary to solve possibly hard integer linear programs, it has the advantage that more detailed mechanistic questions can be formulated. It is thus possible to query networks for general transformation motifs, and to automatically enumerate optimal and near-optimal pathways. Similarities and differences between our work and traditional approaches in metabolic network analysis are discussed in detail. To demonstrate the applicability of the mathematical framework to real-life problems we first explore the design space of possible non-oxidative glycolysis pathways and show that recent manually designed pathways can be further optimized. We then use a model of sugar chemistry to investigate pathways in the autocatalytic formose process. A graph transformation-based approach is used to automatically generate the reaction networks of interest.

Finding the K best synthesis plans.

In synthesis planning, the goal is to synthesize a target molecule from available starting materials, possibly optimizing costs such as price or environmental impact of the process. Current algorithmic approaches to synthesis planning are usually based on selecting a bond set and finding a single good plan among those induced by it. We demonstrate that synthesis planning can be phrased as a combinatorial optimization problem on hypergraphs by modeling individual synthesis plans as directed hyperpaths embedded in a hypergraph of reactions (HoR) representing the chemistry of interest. As a consequence, a polynomial time algorithm to find the K shortest hyperpaths can be used to compute the K best synthesis plans for a given target molecule. Having K good plans to choose from has many benefits: it makes the synthesis planning process much more robust when in later stages adding further chemical detail, it allows one to combine several notions of cost, and it provides a way to deal with imprecise yield estimates. A bond set gives rise to a HoR in a natural way. However, our modeling is not restricted to bond set based approaches-any set of known reactions and starting materials can be used to define a HoR. We also discuss classical quality measures for synthesis plans, such as overall yield and convergency, and demonstrate that convergency has a built-in inconsistency which could render its use in synthesis planning questionable. Decalin is used as an illustrative example of the use and implications of our results.

Time-consistent reconciliation maps and forbidden time travel.

BACKGROUND: In the absence of horizontal gene transfer it is possible to reconstruct the history of gene families from empirically determined orthology relations, which are equivalent to event-labeled gene trees. Knowledge of the event labels considerably simplifies the problem of reconciling a gene tree T with a species trees S, relative to the reconciliation problem without prior knowledge of the event types. It is well-known that optimal reconciliations in the unlabeled case may violate time-consistency and thus are not biologically feasible. Here we investigate the mathematical structure of the event labeled reconciliation problem with horizontal transfer. RESULTS: We investigate the issue of time-consistency for the event-labeled version of the reconciliation problem, provide a convenient axiomatic framework, and derive a complete characterization of time-consistent reconciliations. This characterization depends on certain weak conditions on the event-labeled gene trees that reflect conditions under which evolutionary events are observable at least in principle. We give an [Formula: see text]-time algorithm to decide whether a time-consistent reconciliation map exists. It does not require the construction of explicit timing maps, but relies entirely on the comparably easy task of checking whether a small auxiliary graph is acyclic. The algorithms are implemented in C++ using the boost graph library and are freely available at https://github.com/Nojgaard/tc-recon. SIGNIFICANCE: The combinatorial characterization of time consistency and thus biologically feasible reconciliation is an important step towards the inference of gene family histories with horizontal transfer from orthology data, i.e., without presupposed gene and species trees. The fast algorithm to decide time consistency is useful in a broader context because it constitutes an attractive component for all tools that address tree reconciliation problems.

An intermediate level of abstraction for computational systems chemistry.

Computational techniques are required for narrowing down the vast space of possibilities to plausible prebiotic scenarios, because precise information on the molecular composition, the dominant reaction chemistry and the conditions for that era are scarce. The exploration of large chemical reaction networks is a central aspect in this endeavour. While quantum chemical methods can accurately predict the structures and reactivities of small molecules, they are not efficient enough to cope with large-scale reaction systems. The formalization of chemical reactions as graph grammars provides a generative system, well grounded in category theory, at the right level of abstraction for the analysis of large and complex reaction networks. An extension of the basic formalism into the realm of integer hyperflows allows for the identification of complex reaction patterns, such as autocatalysis, in large reaction networks using optimization techniques.This article is part of the themed issue 'Reconceptualizing the origins of life'.

Generic strategies for chemical space exploration.

The chemical universe of molecules reachable from a set of start compounds by iterative application of a finite number of reactions is usually so vast, that sophisticated and efficient exploration strategies are required to cope with the combinatorial complexity. A stringent analysis of (bio)chemical reaction networks, as approximations of these complex chemical spaces, forms the foundation for the understanding of functional relations in Chemistry and Biology. Graphs and graph rewriting are natural models for molecules and reactions. Borrowing the idea of partial evaluation from functional programming, we introduce partial applications of rewrite rules. A framework for the specification of exploration strategies in graph-rewriting systems is presented. Using key examples of complex reaction networks from carbohydrate chemistry we demonstrate the feasibility of this high-level strategy framework. While being designed for chemical applications, the framework can also be used to emulate higher-level transformation models such as illustrated in a small puzzle game.

A parameter-adaptive dynamic programming approach for inferring cophylogenies.

BACKGROUND: Coevolutionary systems like hosts and their parasites are commonly used model systems for evolutionary studies. Inferring the coevolutionary history based on given phylogenies of both groups is often done by employing a set of possible types of events that happened during coevolution. Costs are assigned to the different types of events and a reconstruction of the common history with a minimal sum of event costs is sought. RESULTS: This paper introduces a new algorithm and a corresponding tool called CoRe-PA, that can be used to infer the common history of coevolutionary systems. The proposed method utilizes an event-based concept for reconciliation analyses where the possible events are cospeciations, sortings, duplications, and (host) switches. All known event-based approaches so far assign costs to each type of cophylogenetic events in order to find a cost-minimal reconstruction. CoRe-PA uses a new parameter-adaptive approach, i.e., no costs have to be assigned to the coevolutionary events in advance. Several biological coevolutionary systems that have already been studied intensely in literature are used to show the performance of CoRe-PA. CONCLUSION: From a biological point of view reasonable cost values for event-based reconciliations can often be estimated only very roughly. CoRe-PA is very useful when it is difficult or impossible to assign exact cost values to different types of coevolutionary events in advance.

Extended shapes for the combinatorial design of RNA sequences.

It is known that for two given secondary structures (defined by position of base pairings) an RNA string can easily be found that can fold into both structures. For more than two secondary structures this is not necessarily possible. In this paper, we introduce pseudo edges that are used to forbid that certain base pairs can bind and therefore can be used to define the properties of possible RNA secondary structures. We study the complexity of the problem to design an RNA sequence that can fold into different secondary structures each of them is described by a set of required and forbidden base pairs. We refine the NP-completeness results of Clote et al. (2005) and show an analogous NP-completeness result for the realisation problem concerning the removal of (pseudo) edges. We also present a polynomial time method for checking the realisability of extended shape graphs. Furthermore, we empirically analyse the influence of pseudo edges on the realisability for sets of random RNA sequences and for sets of aptamers.

Solving the preserving reversal median problem.

Genomic rearrangement operations can be very useful to infer the phylogenetic relationship of gene orders representing species. We study the problem of finding potential ancestral gene orders for the gene orders of given taxa, such that the corresponding rearrangement scenario has a minimal number of reversals, and where each of the reversals has to preserve the common intervals of the given input gene orders. Common intervals identify sets of genes that occur consecutively in all input gene orders. The problem of finding such an ancestral gene order is called the preserving reversal median problem (pRMP). A tree-based data structure for the representation of the common intervals of all input gene orders is used in our exact algorithm TCIP for solving the pRMP. It is known that the minimum number of reversals to transform one gene order into another can be computed in polynomial time, whereas the corresponding problem with the restriction that common intervals should not be destroyed is already NP-hard. It is shown theoretically that TCIP can solve a large class of pRMP instances in polynomial time. Empirically we show the good performance of TCIP on biological and artificial data.

Stability and performance of ant queue inspired task partitioning methods.

In this paper, we consider computing systems that have autonomous helper components which fulfill support functions and that possess reconfigurable hardware so that they can specialize to different types of service tasks. Several self-organized task partitioning methods are proposed that can be used by the helper components to decide how to reconfigure and which service tasks to execute. The proposed task partitioning methods are inspired by the so-called ant queue system that can be found in real ants for partitioning tasks between the individuals. The aim of this study is to investigate basic properties of the task partitioning methods, like stability and efficiency, in order to obtain basic insights into the design of task partitioning methods in self-organized service systems. More precisely, the investigations are threefold: (1) discrete event simulations are used to investigate systems, (2) for a simple version of the task partitioning system analytical stability results are obtained by means of delay differential equation systems and (3) by numerically solving initial value problems.

Evolution of mitochondrial gene orders in echinoderms.

A comprehensive analysis of the mitochondrial gene orders of all previously published and two novel Antedon mediterranea (Crinoidea) and Ophiura albida (Ophiuroidea) complete echinoderm mitochondrial genomes shows that all major types of rearrangement operations are necessary to explain the evolution of mitochondrial genomes. In addition to protein coding genes we include all tRNA genes as well as the control region in our analysis. Surprisingly, 7 of the 16 genomes published in the GenBank database contain misannotations, mostly unannotated tRNAs and/or mistakes in the orientation of tRNAs, which we have corrected here. Although the gene orders of mt genomes appear very different, only 8 events are necessary to explain the evolutionary history of echinoderms with the exception of the ophiuroids. Only two of these rearrangements are inversions, while we identify three tandem-duplication-random-loss events and three transpositions.

CREx: inferring genomic rearrangements based on common intervals.

SUMMARY: We present the web-based program CREx for heuristically determining pairwise rearrangement events in unichromosomal genomes. CREx considers transpositions, reverse transpositions, reversals and tandem-duplication-random-loss (TDRL) events. It supports the user in finding parsimonious rearrangement scenarios given a phylogenetic hypothesis. CREx is based on common intervals, which reflect genes that appear consecutively in several of the input gene orders. AVAILABILITY: CREx is freely available at http://pacosy.informatik.uni-leipzig.de/crex

Using median sets for inferring phylogenetic trees.

MOTIVATION: Algorithms for phylogenetic tree reconstruction based on gene order data typically repeatedly solve instances of the reversal median problem (RMP) which is to find for three given gene orders a fourth gene order (called median) with a minimal sum of reversal distances. All existing algorithms of this type consider only one median for each RMP instance even when a large number of medians exist. A careful selection of one of the medians might lead to better phylogenetic trees. RESULTS: We propose a heuristic algorithm amGRP for solving the multiple genome rearrangement problem (MGRP) by repeatedly solving instances of the RMP taking all medians into account. Algorithm amGRP uses a branch-and-bound method that branches over medians from a selected subset of all medians for each RMP instance. Different heuristics for selecting the subsets have been investigated. To show that the medians for RMP vary strongly with respect to different properties that are likely to be relevant for phylogenetic tree reconstruction, the set of all medians has been investigated for artificial datasets and mitochondrial DNA (mtDNA) gene orders. Phylogenetic trees have been computed for a large set of randomly generated gene orders and two sets of mtDNA gene order data for different animal taxa with amGRP and with two standard approaches for solving the MGRP (GRAPPA-DCM and MGR). The results show that amGRP outperforms both other methods with respect to solution quality and computation time on the test data. AVAILABILITY: The source code of amGRP, additional results and the test instances used in this paper are freely available from the authors.