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This deliverable presents the final release of demonstration workflows for the BioExcel-2 project, including a wrap-up of all the work done for the BioBB library, its associated workflows, and a final analysis of the milestones achieved from the initial roadmap. The current release of the BioExcel Building Blocks library is presented in the first section, underlining the FAIR development process followed, including the automatic generation of the BioBB adapters from the Python documentation. The current available modules (categories) in the library are listed. Finally, the landing website and its different sections are briefly described. The second section enumerates the final collection of demonstration workflows, with a brief description of what each workflow does, the tools used, and links to the source code and documentation. The library versatility, validated with the collection of demonstration workflows, is explained, and links to the different workflow flavours are presented in a summary table. The power of the pre-exascale demonstration workflows is presented in the fourth section, with examples of workflows successfully applied to real scientific projects (success stories). The following section focuses on the broad range of possibilities to find and execute BioExcel workflows, from local or HPC installations, to web-based interfaces. Visibility and uptake is discussed in the sixth section, listing a number of training events, webinars and scientific drafts with the presence of the library and the demonstration workflows. The final section revisits the proposed roadmap for the WP2, analysing the status of the intended milestones at the end of the project, with comments on the progress, potential issues and redefined tasks.

We introduce the concept of Canonical Workflow Building Blocks (CWBB), a methodology of describing and wrapping computational tools, in order for them to be utilized in a reproducible manner from multiple workflow languages and execution platforms. The concept is implemented and demonstrated with the BioExcel Building Blocks library (BioBB), a collection of tool wrappers in the field of computational biomolecular simulation. Interoperability across different workflow languages is showcased through a protein Molecular Dynamics setup transversal workflow, built using this library and run with 5 different Workflow Manager Systems (WfMS). We argue such practice is a necessary requirement for FAIR Computational Workflows and an element of Canonical Workflow Frameworks for Research (CWFR) in order to improve widespread adoption and reuse of computational methods across workflow language barriers., Revised manuscript submitted to Special issue on Canonical Workflow Frameworks for Research in the journal Data Intelligence.

Modern high-throughput structure-based drug discovery algorithms consider ligand flexibility, but typically with low accuracy, which results in a loss of performance in the derived models. Here we present the bioactive conformational ensemble (BCE) server and its associated database. The server creates conformational ensembles of drug-like ligands and stores them in the BCE database, where a variety of analyses are offered to the user. The workflow implemented in the BCE server combines enhanced sampling molecular dynamics with self-consistent reaction field quantum mechanics (SCRF/QM) calculations. The server automatizes all of the steps to transform one-dimensional (1D) or 2D representation of drugs into 3D molecules, which are then titrated, parametrized, hydrated, and optimized before being subjected to Hamiltonian replica-exchange (HREX) molecular dynamics simulations. Ensembles are collected and subjected to a clustering procedure to derive representative conformers, which are then analyzed at the SCRF/QM level of theory. All structural data are organized in a noSQL database accessible through a graphical interface and in a programmatic manner through a REST API. The server allows the user to define a private workspace and offers a deposition protocol as well as input files for "in house" calculations in those cases where confidentiality is a must. The database and the associated server are available at https://mmb.irbbarcelona.org/BCE.

Modern high-throughput structure-based drug discovery algorithms consider ligand flexibility, but typically with low accuracy, which results in a loss of performance in the derived models. Here we present the Bioactive Conformational Ensemble (BCE) server and its associated database. The server creates conformational ensembles of drug-like ligands and stores them in the BCE database, where a variety of analyses are offered to the user. The workflow implemented in the BCE server combines enhanced sampling molecular dynamics with self-consistent reaction field quantum mechanics (SCRF/QM) calculations. The server automatizes all the steps to transform 1D or 2D representation of drugs into three dimensional molecules, which are then titrated, parametrized, hydrated and optimized before being subjected to Hamiltonian replica-exchange (HREX) molecular dynamics simulations. Ensembles are collected and subjected to a clustering procedure to derive representative conformers, which are then analyzed at the SCRF/QM level of theory. All structural data is organized in a noSQL database accessible through a graphical interface and in a programmatic manner through a REST API. The server allows the user to define a private workspace and offers a deposition protocol as well as input files for "in house" calculations in those cases where confidentiality is a must. The database and the associated server are available at https://mmb.irbbarcelona.org/BCE

This deliverable presents the first release of the workflow-ready BioExcel building blocks library for the BioExcel-2 period. The initial roadmap of the novel identified building blocks presented in D2.1 is revised, and a new, updated roadmap for the rest of the project is presented. The current situation section contains a description of the new release of the BioExcel building blocks library, including the content of the release, the new library modules recently developed, updates on the already existing modules, new functionalities and bug fixes, and work done into increasing its visibility and outreach. The initial and updated roadmap section contains a revision of the initial roadmap presented in the D2.1 document in PM6, highlighting the milestones reached and issues found. From that, an updated roadmap for the development of the software library during the next 2 years is proposed, including a large set of new building blocks.

Multiscale Genomics (MuG) Virtual Research Environment (MuGVRE) is a cloud-based computational infrastructure created to support the deployment of software tools addressing the various levels of analysis in 3D/4D genomics. Integrated tools tackle needs ranging from high computationally demanding applications (e.g. molecular dynamics simulations) to high-throughput data analysis applications (like the processing of next generation sequencing). The MuG Infrastructure is based on openNebula cloud systems implemented at the Institute for research in Biomedicine, and the Barcelona Supercomputing Center, and has specific interfaces for users and developers. Interoperability of the tools included in MuGVRE is maintained through a rich set of metadata allowing the system to associate tools and data in a transparent manner. Execution scheduling is based in a traditional queueing system to handle demand peaks in applications of fixed needs, and an elastic and multi-scale programming model (pyCOMPSs, controlled by the PMES scheduler), for complex workflows requiring distributed or multi-scale executions schemes. MuGVRE is available athttps://vre.multiscalegenomics.euand documentation and general information athttps://www.multiscalegenomics.eu. The infrastructure is open and freely accessible.

We present Nucleosome Dynamics, a suite of programs integrated into a virtual research environment and created to define nucleosome architecture and dynamics from noisy experimental data. The package allows both the definition of nucleosome architectures and the detection of changes in nucleosomal organization due to changes in cellular conditions. Results are displayed in the context of genomic information thanks to different visualizers and browsers, allowing the user a holistic, multidimensional view of the genome/transcriptome. The package shows good performance for both locating equilibrium nucleosome architecture and nucleosome dynamics and provides abundant useful information in several test cases, where experimental data on nucleosome position (and for some cases expression level) have been collected for cells under different external conditions (cell cycle phase, yeast metabolic cycle progression, changes in nutrients or difference in MNase digestion level). Nucleosome Dynamics is a free software and is provided under several distribution models. M.O. is an ICREA (Institució Catalana de Recerca i Estudis Avancats) academia researcher; Spanish Ministry of Science [RTI2018-096704-B-100]; Catalan Government [2017-SGR-134]; Instituto de Salud Carlos III–Instituto Nacional de Bioinformática, the European Union's Horizon 2020 research and innovation program, and the Biomolecular and Bioinformatics Resources Platform [ISCIII PT 17/0009/0007 co-funded by the Fondo Europeo de Desarrollo Regional FEDER; Grants Elixir-Excelerate: 676559 and BioExcel2: 823830; ERC:812850; MuG-676566]; MINECO Severo Ochoa Award of Excellence from the Government of Spain (awarded to IRB Barcelona). Funding for open access charge: Spanish Ministry of Science [RTI2018-096704-B-100].

We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence. We characterize the sequence-dependent choreography of backbone and base movements modulating the non-Gaussian or anharmonic effects manifested in the higher moments of the dynamics of the duplex when sampling the equilibrium distribution. Contrary to prior assumptions, such anharmonic deformations are not rare in DNA and can play a significant role in determining DNA conformation within complexes. Polymorphisms in helical geometries are particularly prevalent for certain tetranucleotide sequence contexts and are always coupled to a complex network of coordinated changes in the backbone. The analysis of our simulations, which contain instances of all tetranucleotide sequences, allow us to extend Calladine–Dickerson rules used for decades to interpret the average geometry of DNA, leading to a set of rules with quantitative predictive power that encompass nonlocal sequence-dependence and anharmonic fluctuations.

We present a new coarse grained method for the simulation of duplex DNA. The algorithm uses a generalized multi-harmonic model that can represent any multi-normal distribution of helical parameters, thus avoiding caveats of current mesoscopic models for DNA simulation and representing a breakthrough in the field. The method has been parameterized from accurate parmbsc1 atomistic molecular dynamics simulations of all unique tetranucleotide sequences of DNA embedded in long duplexes and takes advantage of the correlation between helical states and backbone configurations to derive atomistic representations of DNA. The algorithm, which is implemented in a simple web interface and in a standalone package reproduces with high computational efficiency the structural landscape of long segments of DNA untreatable by atomistic molecular dynamics simulations.