key: cord-0818214-vaak0siv
authors: Macias, Jose Ramon; Sanchez-Garcia, Ruben; Conesa, Pablo; Ramirez-Aportela, Erney; Martinez Gonzalez, Marta; Wert-Carvajal, Carlos; Parra-Perez, Alberto M; Segura Mora, Joan; Horrell, Sam; Thorn, Andrea; Sorzano, Carlos O S; Carazo, Jose Maria
title: 3DBionotes COVID-19 Edition
date: 2021-05-20
journal: Bioinformatics
DOI: 10.1093/bioinformatics/btab397
sha: e0dfd3198b55e2fc20cf419ea0c2098aea7425e1
doc_id: 818214
cord_uid: vaak0siv

SUMMARY: The web platform 3DBionotes-WS integrates multiple Web Services and an interactive Web Viewer to provide a unified environment in which biological annotations can be analyzed in their structural context. Since the COVID-19 outbreak, new structural data from many viral proteins have been provided at a very fast pace. This effort includes many cryogenic Electron Microscopy (cryo-EM) studies, together with more traditional ones (X-rays, NMR), using several modeling approaches and complemented with structural predictions. At the same time, a plethora of new genomics and interactomics information (including fragment screening and structure-based virtual screening efforts) have been made available from different servers. In this context we have developed 3DBionotes-COVID-19 as an answer to: (1) The need to explore multi-omics data in a unified context with a special focus on structural information and (2) the drive to incorporate quality measurements, especially in the form of advanced validation metrics for cryogenic Electron Microscopy. AVAILABILITY: https://3dbionotes.cnb.csic.es/ws/covid19 SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The 3DBionotes-WS web platform has been operational for several years as part of the online offer of the Spanish Institute of Bioinformatics, the Spanish Node of the Research Infrastructure (RI) ELIXIR and Instruct-ERIC RI (Segura et al., 2019) . It is, in fact, one of ELIXIR Recommended Interoperability Resources (https://elixireurope.org/platforms/interoperability/rirs). A major goal is to provide an interactive graphical environment over the web where structural and multi-omics data can be intuitively explored, complemented by a powerful API.

The COVID-19 outbreak has changed science: worldwide, scientists came together across disciplines and national borders in order to fight the pandemic. Structural biologists are no exception and the role of cryogenic electron microscopy (cryo-EM) in elucidating key viral structures is paramount (for a brief outline, see (Kearns, 2020) ), complementing more traditional approaches such as X-ray crystallography, NMR and fold predictions. However, SARS-CoV-2 maps didn't achieve very high resolution (in most cases close to 3Å, particularly for cryo-EM), which made it difficult to build atomic models suitable for drug development.

Additionally, the pressure to publish these structures as fast as possible has never been so high. Early in the pandemic, specific resources have been created to address structural needs (https://github.com/thornlab/coronavirus_structural_task_force), acknowledging the requirement to pay special attention not only to data quantity, but also to data quality. In this way, validation information on cryo-EM maps provided by the Coronavirus Structural Task Force has been integrated into 3DBionotes, which have evolved to supply quality measurements, keeping its orientation towards the web (and its API) and focusing on integrative analysis. Indeed, its COVID-19 edition described here, combines in the same analysis framework key viral genomics, interactomics and structural information, including drug screening approaches (both experimental fragment-based screening (Douangamath et al., 2020) and virtual screening). In the following, we describe 3DBionotes-COVID-19 edition, illustrating its use and value for users with some case studies in the Supplementary Material. 

The design of 3DBionotes-COVID-19 adds an additional layer of interactive information over the classical design of 3DBionotes. The new edition has a specific landing page to manage multiple sources of structural information that, once selected, launches a new version of 3DBionotes accessing COVID-19 specific information (see Figure 1 ). We describe this design in the following:

This page acts as a structural information organizer, collecting data from SARS-CoV-2 and related coronavirus, as well as their interactions with host proteins. We automatically harvest structures deposited in PDB and EMDB together with predicted models from SWISSModel (Bienert et al., 2017) , AlphaFold (Jumper,J. Et al., 2020) and BSM-Arc (Hijikata,A. et al., 2020) . When validation and quality information is available from PDB-REDO (Joosten et al., 2014) and the Coronavirus Structural Task Force (Croll et al., 2020) special tags are incorporated for every entry, pointing to the re-refined models. Entries are organized into five categories: PDB, EMDB, Interactions with other proteins (PPI) and Ligands, Related (to SARS-CoV or others) and Computational Models. In "Ligands" we initially incorporate experimental information from fragment-based screening (Douangamath et al., 2020) as well as our own structure-based repurposing virtual screening (https://covid19drugrepurposing.cnb.csic.es).

Every entry is displayed with its reference and a static view of the model, when available, that serves the user as a preliminary visual hint of the structure (Fig.1 A) . A pop-up panel is displayed with a brief description of the entry and a set of external links when the pointer is placed on the image for a few moments. Upon clicking on the entry, data is transferred to a new instance of 3DBionotes that pays special attention to multi-omics and cryoEM quality information, as detailed in the next section, opening the 3D Viewer (Fig.1 B) and starting the annotation collection process. Users can go back to the landing page at any time in their analysis. By clicking in any of the symbols representing an annotation, all the residues associated with it will be highlighted in the protein sequence alignment as well as in the atomic structure. At the same time, those residues will also be highlighted with vertical yellow bars so it is easier to locate in relation with other annotations types. Additionally, a panel will pop-up with more detailed information about the annotation, including links to the origin of the data source.

3DBionotes-WS, in general, collects and organizes a wide range of annotations of the selected macromolecule. The COVID-19 release includes access to a collection of specifically developed servers adding new functionality, as it can be appreciated in the case studies detailed in Supplemental Material. Among them, we highlight:

• Cryo-EM quality information at the amino acid level coloring the map being displayed in the 3D Viewer, including:

• Local resolution information on cryo-EM maps, calculated using a deep learning approach which does not require half maps (Ramírez-Aportela et al., 2019). • Quantitative validation metrics, such as Q-scores (Pintilie et al., 2020) and FSC-Q scores (Ramírez-Aportela et al., 2021). • SARS-CoV-2 main protease fragment screening by PanDDA analysis (Pearce et al., 2017) . • Genomics variants, with source data from CNCB (https://bigd.big.ac.cn/ncov/variation). • Functional mapping of Protein-Protein Interactions (PPI), with source data from Korbin's lab (http://draco.cs.wpi.edu/wuhan) (Srinivasan et al., 2020) .

In the Supplementary Material we present how 3DBionotes can be used in four different use cases, namely:

(1) SARS-CoV-2 spike protein cryo-EM map validation analysis based on local resolution metrics.

(1) Use of improved structural models using new refinement methods collected from the Coronavirus Structural Task Force.

(2) Analysis of SARS-CoV-2 spike variant D614G.

(1) Study of drug screening on SARS-CoV-2 main protease (NSP5).

is fully accessible at https://3dbionotes.cnb.csic.es/ws/covid19, providing a unique analysis environment tailored to COVID-19 information. It has all the advantages of 3DBionotes in terms of complex interactive analysis over the Web and API access, offering both the possibility to work with structural data already deposited in public databases and with new user data, plus a series of new services geared towards quality (cryo-EM validation and curated structural models) and information integration. We demonstrate the usefulness of this interactive resource on four selected cases. 

The SWISS-MODEL Repository-new features and functionality

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease

Knowledge-based structural models of SARS-CoV-2 proteins and their complexes with potential drugs

The PDB_REDO server for macromolecular structure model optimization

Computational predictions of protein structures associated with COVID-19. Version 3, DeepMind website

Structure of the Pandemic

A multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density

Measurement of atom resolvability in cryo-EM maps with Q-scores

DeepRes: a new deep-learning-and aspect-based local resolution method for electron-microscopy maps

FSC-Q: A CryoEM map-to-atomic model quality validation based on the local Fourier Shell Correlation

3DBIONOTES v3.0: crossing molecular and structural biology data with genomic variations

Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins