Using interactive Jupyter Notebooks and BioConda for FAIR and reproducible biomolecular simulation workflows.

Interactive Jupyter Notebooks in combination with Conda environments can be used to generate FAIR (Findable, Accessible, Interoperable and Reusable/Reproducible) biomolecular simulation workflows. The interactive programming code accompanied by documentation and the possibility to inspect intermediate results with versatile graphical charts and data visualization is very helpful, especially in iterative processes, where parameters might be adjusted to a particular system of interest. This work presents a collection of FAIR notebooks covering various areas of the biomolecular simulation field, such as molecular dynamics (MD), protein-ligand docking, molecular checking/modeling, molecular interactions, and free energy perturbations. Workflows can be launched with myBinder or easily installed in a local system. The collection of notebooks aims to provide a compilation of demonstration workflows, and it is continuously updated and expanded with examples using new methodologies and tools.

A new paradigm for molecular dynamics databases: the COVID-19 database, the legacy of a titanic community effort.

Molecular dynamics (MD) simulations are keeping computers busy around the world, generating a huge amount of data that is typically not open to the scientific community. Pioneering efforts to ensure the safety and reusability of MD data have been based on the use of simple databases providing a limited set of standard analyses on single-short trajectories. Despite their value, these databases do not offer a true solution for the current community of MD users, who want a flexible analysis pipeline and the possibility to address huge non-Markovian ensembles of large systems. Here we present a new paradigm for MD databases, resilient to large systems and long trajectories, and designed to be compatible with modern MD simulations. The data are offered to the community through a web-based graphical user interface (GUI), implemented with state-of-the-art technology, which incorporates system-specific analysis designed by the trajectory providers. A REST API and associated Jupyter Notebooks are integrated into the platform, allowing fully customized meta-analysis by final users. The new technology is illustrated using a collection of trajectories obtained by the community in the context of the effort to fight the COVID-19 pandemic. The server is accessible at https://bioexcel-cv19.bsc.es/#/. It is free and open to all users and there are no login requirements. It is also integrated into the simulations section of the BioExcel-MolSSI COVID-19 Molecular Structure and Therapeutics Hub: https://covid.molssi.org/simulations/ and is part of the MDDB effort (https://mddbr.eu).

Sequence-Dependent Properties of the RNA Duplex.

Sequence-dependent properties of the DNA duplex have been accurately described using extensive molecular dynamics simulations. The RNA duplex meanwhile─which is typically represented as a sequence-averaged rigid rod─does not benefit from having equivalent molecular dynamics simulations. In this paper, we present a massive simulation effort using a set of ABC-optimized duplexes from which we derived tetramer-resolution properties of the RNA duplex and a simple mesoscopic model that can represent elastic properties of long RNA duplexes. Despite the extreme chemical similarity between DNA and RNA, the local and global elastic properties of the duplexes are very different. DNA duplexes show a complex and nonelastic pattern of flexibility, for instance, while RNA duplexes behave as an elastic system whose deformations can be represented by simple harmonic potentials. In RNA duplexes (RNA2), not only are intra- and interbase pair parameters (equilibrium and mechanical) different from those in the equivalent DNA duplex sequences (DNA2) but the correlations between movements also differ. Simple statements on the relative flexibility or stability of both polymers are meaningless and should be substituted by a more detailed description depending on the sequence and the type of deformation considered.

High-Throughput Prediction of the Impact of Genetic Variability on Drug Sensitivity and Resistance Patterns for Clinically Relevant Epidermal Growth Factor Receptor Mutations from Atomistic Simulations.

Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) can be drivers of cancer and also trigger drug resistance in patients receiving chemotherapy treatment based on kinase inhibitors. A priori knowledge of the impact of EGFR variants on drug sensitivity would help to optimize chemotherapy and design new drugs that are effective against resistant variants before they emerge in clinical trials. To this end, we explored a variety of in silico methods, from sequence-based to "state-of-the-art" atomistic simulations. We did not find any sequence signal that can provide clues on when a drug-related mutation appears or the impact of such mutations on drug activity. Low-level simulation methods provide limited qualitative information on regions where mutations are likely to cause alterations in drug activity, and they can predict around 70% of the impact of mutations on drug efficiency. High-level simulations based on nonequilibrium alchemical free energy calculations show predictive power. The integration of these "state-of-the-art" methods into a workflow implementing an interface for parallel distribution of the calculations allows its automatic and high-throughput use, even for researchers with moderate experience in molecular simulations.

Pre-exascale HPC approaches for molecular dynamics simulations. Covid-19 research: A use case.

Exascale computing has been a dream for ages and is close to becoming a reality that will impact how molecular simulations are being performed, as well as the quantity and quality of the information derived for them. We review how the biomolecular simulations field is anticipating these new architectures, making emphasis on recent work from groups in the BioExcel Center of Excellence for High Performance Computing. We exemplified the power of these simulation strategies with the work done by the HPC simulation community to fight Covid-19 pandemics. This article is categorized under:Data Science > Computer Algorithms and ProgrammingData Science > Databases and Expert SystemsMolecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods.

BioExcel Building Blocks Workflows (BioBB-Wfs), an integrated web-based platform for biomolecular simulations.

We present BioExcel Building Blocks Workflows, a web-based graphical user interface (GUI) offering access to a collection of transversal pre-configured biomolecular simulation workflows assembled with the BioExcel Building Blocks library. Available workflows include Molecular Dynamics setup, protein-ligand docking, trajectory analyses and small molecule parameterization. Workflows can be launched in the platform or downloaded to be run in the users' own premises. Remote launching of long executions to user's available High-Performance computers is possible, only requiring configuration of the appropriate access credentials. The web-based graphical user interface offers a high level of interactivity, with integration with the NGL viewer to visualize and check 3D structures, MDsrv to visualize trajectories, and Plotly to explore 2D plots. The server requires no login but is recommended to store the users' projects and manage sensitive information such as remote credentials. Private projects can be made public and shared with colleagues with a simple URL. The tool will help biomolecular simulation users with the most common and repetitive processes by means of a very intuitive and interactive graphical user interface. The server is accessible at https://mmb.irbbarcelona.org/biobb-wfs.

BioExcel Building Blocks REST API (BioBB REST API), programmatic access to interoperable biomolecular simulation tools.

MOTIVATION: The BioExcel Building Blocks (BioBB) library offers a broad collection of wrappers on top of common biomolecular simulation and bioinformatics tools. The possibility to access the library remotely and programmatically increases its usability, allowing individual and sporadic executions and enabling remote workflows. RESULTS: BioBB REST API extends and complements the BioBB library offering programmatic access to the collection of biomolecular simulation tools included in the BioExcel Building Blocks library. Molecular Dynamics setup, docking, structure modeling, free energy simulations and flexibility analyses are examples of functionalities included in the endpoints collection. All functionalities are accessible through standard REST API calls, voiding the need for tool installation. AVAILABILITY AND IMPLEMENTATION: All the information related to the BioBB REST API endpoints is accessible from https://mmb.irbbarcelona.org/biobb-api/. Links to extended documentation, including OpenAPI endpoints specification and examples, Read-The-Docs documentation and a complete workflow tutorial can be found in the Supplementary Table S1. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

3dRS, a Web-Based Tool to Share Interactive Representations of 3D Biomolecular Structures and Molecular Dynamics Trajectories.

3D Representation Sharing (3dRS) is a web-based tool designed to share biomolecular structure representations, including 4D ensembles derived from Molecular Dynamics (MD) trajectories. The server offers a team working in different locations a single URL to share and discuss structural data in an interactive fashion, with the possibility to use it as a live figure for scientific papers. The web tool allows an easy upload of structures and trajectories in different formats. The 3D representation, powered by NGL viewer, offers an interactive display with smooth visualization in modern web browsers. Multiple structures can be loaded and superposed in the same scene. 1D sequences from the loaded structures are presented and linked to the 3D representation. Multiple, pre-defined 3D molecular representations are available. The powerful NGL selection syntax allows the definition of molecular regions that can be then displayed using different representations. Important descriptors such as distances or interactions can be easily added into the representation. Trajectory frames can be explored using a common video player control panel. Trajectories are efficiently stored and transferred to the NGL viewer thanks to an MDsrv-based data streaming. The server design offers all functionalities in one single web page, with a curated user experience, involving a minimum learning curve. Extended documentation is available, including a gallery with a collection of scenes. The server requires no registration and is available at https://mmb.irbbarcelona.org/3dRS.

Sequence-dependent structural properties of B-DNA: what have we learned in 40 years?

The structure of B-DNA, the physiological form of the DNA molecule, has been a central topic in biology, chemistry and physics. Far from uniform and rigid, the double helix was revealed as a flexible and structurally polymorphic molecule. Conformational changes that lead to local and global changes in the helix geometry are mediated by a complex choreography of base and backbone rearrangements affecting the ability of the B-DNA to recognize ligands and consequently on its functionality. In this sense, the knowledge obtained from the sequence-dependent structural properties of B-DNA has always been thought crucial to rationalize how ligands and, most notably, proteins recognize B-DNA and modulate its activity, i.e. the structural basis of gene regulation. Honouring the anniversary of the first high-resolution X-ray structure of a B-DNA molecule, in this contribution, we present the most important discoveries of the last 40 years on the sequence-dependent structural and dynamical properties of B-DNA, from the early beginnings to the current frontiers in the field.

Exploring the Conformational Landscape of Bioactive Small Molecules.

By using a combination of classical Hamiltonian replica exchange with high-level quantum mechanical calculations on more than one hundred drug-like molecules, we explored here the energy cost associated with binding of drug-like molecules to target macromolecules. We found that, in general, the drug-like molecules present bound to proteins in the Protein Data Bank (PDB) can access easily the bioactive conformation and in fact for 73% of the studied molecules the "bioactive" conformation is within 3kBT from the most-stable conformation in solution as determined by DFT/SCRF calculations. Cases with large differences between the most-stable and the bioactive conformations appear in ligands recognized by ionic contacts, or very large structures establishing many favorable interactions with the protein. There are also a few cases where we observed a non-negligible uncertainty related to the experimental structure deposited in PDB. Remarkably, the rough automatic force field used here provides reasonable estimates of the conformational ensemble of drugs in solution. The outlined protocol can be used to better estimate the cost of adopting the bioactive conformation.

Bioactive Conformational Ensemble Server and Database. A Public Framework to Speed Up In Silico Drug Discovery.

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.

DFFR: A New Method for High-Throughput Recalibration of Automatic Force-Fields for Drugs.

We present drug force-field recalibration (DFFR), a new method for refining of automatic force-fields used to represent small drugs in docking and molecular dynamics simulations. The method is based on fine-tuning of torsional terms to obtain ensembles that reproduce observables derived from reference data. DFFR is fast and flexible and can be easily automatized for a high-throughput regime, making it useful in drug-design projects. We tested the performance of the method in a few model systems and also in a variety of druglike molecules using reference data derived from: (i) density functional theory coupled to a self-consistent reaction field (DFT/SCRF) calculations on highly populated conformers and (ii) enhanced sampling quantum mechanical/molecular mechanics (QM/MM) where the drug is reproduced at the QM level, while the solvent is represented by classical force-fields. Extension of the method to include other sources of reference data is discussed.

A community proposal to integrate structural bioinformatics activities in ELIXIR (3D-Bioinfo Community).

Structural bioinformatics provides the scientific methods and tools to analyse, archive, validate, and present the biomolecular structure data generated by the structural biology community. It also provides an important link with the genomics community, as structural bioinformaticians also use the extensive sequence data to predict protein structures and their functional sites. A very broad and active community of structural bioinformaticians exists across Europe, and 3D-Bioinfo will establish formal platforms to address their needs and better integrate their activities and initiatives. Our mission will be to strengthen the ties with the structural biology research communities in Europe covering life sciences, as well as chemistry and physics and to bridge the gap between these researchers in order to fully realize the potential of structural bioinformatics. Our Community will also undertake dedicated educational, training and outreach efforts to facilitate this, bringing new insights and thus facilitating the development of much needed innovative applications e.g. for human health, drug and protein design. Our combined efforts will be of critical importance to keep the European research efforts competitive in this respect. Here we highlight the major European contributions to the field of structural bioinformatics, the most pressing challenges remaining and how Europe-wide interactions, enabled by ELIXIR and its platforms, will help in addressing these challenges and in coordinating structural bioinformatics resources across Europe. In particular, we present recent activities and future plans to consolidate an ELIXIR 3D-Bioinfo Community in structural bioinformatics and propose means to develop better links across the community. These include building new consortia, organising workshops to establish data standards and seeking community agreement on benchmark data sets and strategies. We also highlight existing and planned collaborations with other ELIXIR Communities and other European infrastructures, such as the structural biology community supported by Instruct-ERIC, with whom we have synergies and overlapping common interests.

Molywood: streamlining the design and rendering of molecular movies.

MOTIVATION: High-quality dynamic visuals are needed at all levels of science communication, from the conference hall to the classroom. As scientific journals embrace new article formats, many key concepts-particularly, in structural biology-are also more easily conveyed as videos than still frames. Notwithstanding, the design and rendering of a complex molecular movie remain an arduous task. Here, we introduce Molywood, a robust and intuitive tool that builds on the capabilities of Visual Molecular Dynamics (VMD) to automate all stages of movie rendering. RESULTS: Molywood is a Python-based script that uses an integrated workflow to give maximal flexibility in movie design. It implements the basic concepts of actions, layers, grids and concurrency and requires no programming experience to run. AVAILABILITY AND IMPLEMENTATION: The script is freely available on GitLab (gitlab.com/KomBioMol/molywood) and PyPI (through pip), and features an extended documentation, tutorial and gallery hosted on mmb.irbbarcelona.org/molywood.

A multi-modal coarse grained model of DNA flexibility mappable to the atomistic level.

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.

The static and dynamic structural heterogeneities of B-DNA: extending Calladine-Dickerson rules.

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.

Nucleosome Dynamics: a new tool for the dynamic analysis of nucleosome positioning.

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.

BioExcel Building Blocks, a software library for interoperable biomolecular simulation workflows.

In the recent years, the improvement of software and hardware performance has made biomolecular simulations a mature tool for the study of biological processes. Simulation length and the size and complexity of the analyzed systems make simulations both complementary and compatible with other bioinformatics disciplines. However, the characteristics of the software packages used for simulation have prevented the adoption of the technologies accepted in other bioinformatics fields like automated deployment systems, workflow orchestration, or the use of software containers. We present here a comprehensive exercise to bring biomolecular simulations to the "bioinformatics way of working". The exercise has led to the development of the BioExcel Building Blocks (BioBB) library. BioBB's are built as Python wrappers to provide an interoperable architecture. BioBB's have been integrated in a chain of usual software management tools to generate data ontologies, documentation, installation packages, software containers and ways of integration with workflow managers, that make them usable in most computational environments.

How B-DNA Dynamics Decipher Sequence-Selective Protein Recognition.

The rules governing sequence-specific DNA-protein recognition are under a long-standing debate regarding the prevalence of base versus shape readout mechanisms to explain sequence specificity and of the conformational selection versus induced fit binding paradigms to explain binding-related conformational changes in DNA. Using a combination of atomistic simulations on a subset of representative sequences and mesoscopic simulations at the protein-DNA interactome level, we demonstrate the prevalence of the shape readout model in determining sequence-specificity and of the conformational selection paradigm in defining the general mechanism for binding-related conformational changes in DNA. Our results suggest that the DNA uses a double mechanism to adapt its structure to the protein: it moves along the easiest deformation modes to approach the bioactive conformation, while final adjustments require localized rearrangements at the base-pair step and backbone level. Our study highlights the large impact of B-DNA dynamics in modulating DNA-protein binding.

Modulation of the helical properties of DNA: next-to-nearest neighbour effects and beyond.

We used extensive molecular dynamics simulations to study the structural and dynamic properties of the central d(TpA) step in the highly polymorphic d(CpTpApG) tetranucleotide. Contrary to the assumption of the dinucleotide-model and its nearest neighbours (tetranucleotide-model), the properties of the central d(TpA) step change quite significantly dependent on the next-to-nearest (hexanucleotide) sequence context and in a few cases are modulated by even remote neighbours (beyond next-to-nearest from the central TpA). Our results highlight the existence of previously undescribed dynamical mechanisms for the transmission of structural information into the DNA and demonstrate the existence of certain sequences with special physical properties that can impact on the global DNA structure and dynamics.