IHMCIF: An Extension of the PDBx/mmCIF Data Standard for Integrative Structure Determination Methods.

IHMCIF (github.com/ihmwg/IHMCIF) is a data information framework that supports archiving and disseminating macromolecular structures determined by integrative or hybrid modeling (IHM), and making them Findable, Accessible, Interoperable, and Reusable (FAIR). IHMCIF is an extension of the Protein Data Bank Exchange/macromolecular Crystallographic Information Framework (PDBx/mmCIF) that serves as the framework for the Protein Data Bank (PDB) to archive experimentally determined atomic structures of biological macromolecules and their complexes with one another and small molecule ligands (e.g., enzyme cofactors and drugs). IHMCIF serves as the foundational data standard for the PDB-Dev prototype system, developed for archiving and disseminating integrative structures. It utilizes a flexible data representation to describe integrative structures that span multiple spatiotemporal scales and structural states with definitions for restraints from a variety of experimental methods contributing to integrative structural biology. The IHMCIF extension was created with the benefit of considerable community input and recommendations gathered by the Worldwide Protein Data Bank (wwPDB) Task Force for Integrative or Hybrid Methods (wwpdb.org/task/hybrid). Herein, we describe the development of IHMCIF to support evolving methodologies and ongoing advancements in integrative structural biology. Ultimately, IHMCIF will facilitate the unification of PDB-Dev data and tools with the PDB archive so that integrative structures can be archived and disseminated through PDB.

Structural highlights of macromolecular complexes and assemblies.

The structures of macromolecular assemblies have given us deep insights into cellular processes and have profoundly impacted biological research and drug discovery. We highlight the structures of macromolecular assemblies that have been modeled using integrative and computational methods and describe how open access to these structures from structural archives has empowered the research community. The arsenal of experimental and computational methods for structure determination ensures a future where whole organelles and cells can be modeled.

The Nucleic Acid Knowledgebase: a new portal for 3D structural information about nucleic acids.

The Nucleic Acid Knowledgebase (nakb.org) is a new data resource, updated weekly, for experimentally determined 3D structures containing DNA and/or RNA nucleic acid polymers and their biological assemblies. NAKB indexes nucleic acid-containing structures derived from all major structure determination methods (X-ray, NMR and EM), including all held by the Protein Data Bank (PDB). As the planned successor to the Nucleic Acid Database (NDB), NAKB's design preserves all functionality of the NDB and provides novel nucleic acid-centric content, including structural and functional annotations, as well as annotations from and links to external resources. A variety of custom interactive tools have been developed to enable rapid exploration and drill-down of NAKB's content.

ModelCIF: An Extension of PDBx/mmCIF Data Representation for Computed Structure Models.

ModelCIF (github.com/ihmwg/ModelCIF) is a data information framework developed for and by computational structural biologists to enable delivery of Findable, Accessible, Interoperable, and Reusable (FAIR) data to users worldwide. ModelCIF describes the specific set of attributes and metadata associated with macromolecular structures modeled by solely computational methods and provides an extensible data representation for deposition, archiving, and public dissemination of predicted three-dimensional (3D) models of macromolecules. It is an extension of the Protein Data Bank Exchange / macromolecular Crystallographic Information Framework (PDBx/mmCIF), which is the global data standard for representing experimentally-determined 3D structures of macromolecules and associated metadata. The PDBx/mmCIF framework and its extensions (e.g., ModelCIF) are managed by the Worldwide Protein Data Bank partnership (wwPDB, wwpdb.org) in collaboration with relevant community stakeholders such as the wwPDB ModelCIF Working Group (wwpdb.org/task/modelcif). This semantically rich and extensible data framework for representing computed structure models (CSMs) accelerates the pace of scientific discovery. Herein, we describe the architecture, contents, and governance of ModelCIF, and tools and processes for maintaining and extending the data standard. Community tools and software libraries that support ModelCIF are also described.

Electron microscopy holdings of the Protein Data Bank: the impact of the resolution revolution, new validation tools, and implications for the future.

As a discipline, structural biology has been transformed by the three-dimensional electron microscopy (3DEM) "Resolution Revolution" made possible by convergence of robust cryo-preservation of vitrified biological materials, sample handling systems, and measurement stages operating a liquid nitrogen temperature, improvements in electron optics that preserve phase information at the atomic level, direct electron detectors (DEDs), high-speed computing with graphics processing units, and rapid advances in data acquisition and processing software. 3DEM structure information (atomic coordinates and related metadata) are archived in the open-access Protein Data Bank (PDB), which currently holds more than 11,000 3DEM structures of proteins and nucleic acids, and their complexes with one another and small-molecule ligands (~ 6% of the archive). Underlying experimental data (3DEM density maps and related metadata) are stored in the Electron Microscopy Data Bank (EMDB), which currently holds more than 21,000 3DEM density maps. After describing the history of the PDB and the Worldwide Protein Data Bank (wwPDB) partnership, which jointly manages both the PDB and EMDB archives, this review examines the origins of the resolution revolution and analyzes its impact on structural biology viewed through the lens of PDB holdings. Six areas of focus exemplifying the impact of 3DEM across the biosciences are discussed in detail (icosahedral viruses, ribosomes, integral membrane proteins, SARS-CoV-2 spike proteins, cryogenic electron tomography, and integrative structure determination combining 3DEM with complementary biophysical measurement techniques), followed by a review of 3DEM structure validation by the wwPDB that underscores the importance of community engagement.

Protein Data Bank: A Comprehensive Review of 3D Structure Holdings and Worldwide Utilization by Researchers, Educators, and Students.

The Research Collaboratory for Structural Bioinformatics Protein Data Bank (RCSB PDB), funded by the United States National Science Foundation, National Institutes of Health, and Department of Energy, supports structural biologists and Protein Data Bank (PDB) data users around the world. The RCSB PDB, a founding member of the Worldwide Protein Data Bank (wwPDB) partnership, serves as the US data center for the global PDB archive housing experimentally-determined three-dimensional (3D) structure data for biological macromolecules. As the wwPDB-designated Archive Keeper, RCSB PDB is also responsible for the security of PDB data and weekly update of the archive. RCSB PDB serves tens of thousands of data depositors (using macromolecular crystallography, nuclear magnetic resonance spectroscopy, electron microscopy, and micro-electron diffraction) annually working on all permanently inhabited continents. RCSB PDB makes PDB data available from its research-focused web portal at no charge and without usage restrictions to many millions of PDB data consumers around the globe. It also provides educators, students, and the general public with an introduction to the PDB and related training materials through its outreach and education-focused web portal. This review article describes growth of the PDB, examines evolution of experimental methods for structure determination viewed through the lens of the PDB archive, and provides a detailed accounting of PDB archival holdings and their utilization by researchers, educators, and students worldwide.

Crystallographic legacy of Ned Seeman.

We trace the career path of Nadrian Seeman, the inventor of DNA nanotechnology. The influence of his early training in crystallography and how this led to his success in creating self-assembled crystals are highlighted.

Developing Community Resources for Nucleic Acid Structures.

In this review, we describe the creation of the Nucleic Acid Database (NDB) at Rutgers University and how it became a testbed for the current infrastructure of the RCSB Protein Data Bank. We describe some of the special features of the NDB and how it has been used to enable research. Plans for the next phase as the Nucleic Acid Knowledgebase (NAKB) are summarized.

PDBx/mmCIF Ecosystem: Foundational Semantic Tools for Structural Biology.

PDBx/mmCIF, Protein Data Bank Exchange (PDBx) macromolecular Crystallographic Information Framework (mmCIF), has become the data standard for structural biology. With its early roots in the domain of small-molecule crystallography, PDBx/mmCIF provides an extensible data representation that is used for deposition, archiving, remediation, and public dissemination of experimentally determined three-dimensional (3D) structures of biological macromolecules by the Worldwide Protein Data Bank (wwPDB, wwpdb.org). Extensions of PDBx/mmCIF are similarly used for computed structure models by ModelArchive (modelarchive.org), integrative/hybrid structures by PDB-Dev (pdb-dev.wwpdb.org), small angle scattering data by Small Angle Scattering Biological Data Bank SASBDB (sasbdb.org), and for models computed generated with the AlphaFold 2.0 deep learning software suite (alphafold.ebi.ac.uk). Community-driven development of PDBx/mmCIF spans three decades, involving contributions from researchers, software and methods developers in structural sciences, data repository providers, scientific publishers, and professional societies. Having a semantically rich and extensible data framework for representing a wide range of structural biology experimental and computational results, combined with expertly curated 3D biostructure data sets in public repositories, accelerates the pace of scientific discovery. Herein, we describe the architecture of the PDBx/mmCIF data standard, tools used to maintain representations of the data standard, governance, and processes by which data content standards are extended, plus community tools/software libraries available for processing and checking the integrity of PDBx/mmCIF data. Use cases exemplify how the members of the Worldwide Protein Data Bank have used PDBx/mmCIF as the foundation for its pipeline for delivering Findable, Accessible, Interoperable, and Reusable (FAIR) data to many millions of users worldwide.

A new visual design language for biological structures in a cell.

As part of a project to build a spatiotemporal model of the pancreatic ß-cell, we are creating an immersive experience called "World in a Cell" that can be used to integrate and create new educational tools. To do this, we have developed a new visual design language that uses tetrahedral building blocks to express the structural features of biological molecules and organelles in crowded cellular environments. The tetrahedral language enables more efficient animation and user interaction in an immersive environment.

New system for archiving integrative structures.

Structures of many complex biological assemblies are increasingly determined using integrative approaches, in which data from multiple experimental methods are combined. A standalone system, called PDB-Dev, has been developed for archiving integrative structures and making them publicly available. Here, the data standards and software tools that support PDB-Dev are described along with the new and updated components of the PDB-Dev data-collection, processing and archiving infrastructure. Following the FAIR (Findable, Accessible, Interoperable and Reusable) principles, PDB-Dev ensures that the results of integrative structure determinations are freely accessible to everyone.

How the Protein Data Bank changed biology: An introduction to the JBC Reviews thematic series, part 2.

In part 1 of this remarkable collection, we told you the story of The Protein Data Bank (PDB) (1), which was founded 50 years ago, and we illustrated the breadth of the science contained within it with ten informative review articles. The second half of this collection is a continuation of our celebrations to mark this momentous anniversary. Part 2 provides eight more superb articles describing how the PDB has influenced biology over the course of the last half-century and how biology has fueled the deposition of impactful structures in the PDB. Here are some brief synopses of the articles you will enjoy in part 2!

Open-access data: A cornerstone for artificial intelligence approaches to protein structure prediction.

The Protein Data Bank (PDB) was established in 1971 to archive three-dimensional (3D) structures of biological macromolecules as a public good. Fifty years later, the PDB is providing millions of data consumers around the world with open access to more than 175,000 experimentally determined structures of proteins and nucleic acids (DNA, RNA) and their complexes with one another and small-molecule ligands. PDB data users are working, teaching, and learning in fundamental biology, biomedicine, bioengineering, biotechnology, and energy sciences. They also represent the fields of agriculture, chemistry, physics and materials science, mathematics, statistics, computer science, and zoology, and even the social sciences. The enormous wealth of 3D structure data stored in the PDB has underpinned significant advances in our understanding of protein architecture, culminating in recent breakthroughs in protein structure prediction accelerated by artificial intelligence approaches and deep or machine learning methods.

How the Protein Data Bank changed biology: An introduction to the JBC Reviews thematic series, part 1.

This collection of articles celebrates the 50th anniversary of the Protein Data Bank (PDB), the single global digital archive of biological macromolecular structures. The impact of the PDB is immense; we have invited a number of top researchers in structural biology to illustrate its influence on an array of scientific fields. What emerges is a compelling picture of the synergism between the PDB and the explosive progress witnessed in many scientific areas. Availability of reliable, openly accessible, well-archived structural information has arguably had more impact on cell and molecular biology than even some of the enabling technologies such as PCR. We have seen the science move from a time when structural biologists contributed the lion's share of the structures to the PDB and for discussion within their community to a time when any effort to achieve in-depth understanding of a biochemical or cell biological question demands an interdisciplinary approach built atop structural underpinnings.

The data universe of structural biology.

The Protein Data Bank (PDB) has grown from a small data resource for crystallographers to a worldwide resource serving structural biology. The history of the growth of the PDB and the role that the community has played in developing standards and policies are described. This article also illustrates how other biophysics communities are collaborating with the worldwide PDB to create a network of interoperating data resources. This network will expand the capabilities of structural biology and enable the determination and archiving of increasingly complex structures.

Insights from 20 years of the Molecule of the Month.

For 20 years, Molecule of the Month articles have highlighted the functional stories of 3D structures found in the Protein Data Bank (PDB). The PDB is the primary archive of atomic structures of biological molecules, currently providing open access to more than 150,000 structures studied by researchers around the world. The wealth of knowledge embodied in this resource is remarkable, with structures that allow exploration of nearly any biomolecular topic, including the basic science of genetic mechanisms, mechanisms of photosynthesis and bioenergetics, and central biomedical topics like cancer therapy and the fight against infectious disease. The central motivation behind the Molecule of the Month is to provide a user-friendly introduction to this rich body of data, charting a path for users to get started with finding and exploring the many available structures. The Molecule of the Month and related materials are updated regularly at the education portal PDB-101 (http://pdb101.rcsb.org/), offering an ongoing resource for molecular biology educators and students around the world.

Evolving data standards for cryo-EM structures.

Electron cryo-microscopy (cryo-EM) is increasingly being used to determine 3D structures of a broad spectrum of biological specimens from molecules to cells. Anticipating this progress in the early 2000s, an international collaboration of scientists with expertise in both cryo-EM and structure data archiving was established (EMDataResource, previously known as EMDataBank). The major goals of the collaboration have been twofold: to develop the necessary infrastructure for archiving cryo-EM-derived density maps and models, and to promote development of cryo-EM structure validation standards. We describe how cryo-EM data archiving and validation have been developed and jointly coordinated for the Electron Microscopy Data Bank and Protein Data Bank archives over the past two decades, as well as the impact of evolving technology on data standards. Just as for X-ray crystallography and nuclear magnetic resonance, engaging the scientific community via workshops and challenging activities has played a central role in developing recommendations and requirements for the cryo-EM structure data archives.

DNAproDB: an expanded database and web-based tool for structural analysis of DNA-protein complexes.

DNAproDB (https://dnaprodb.usc.edu) is a web-based database and structural analysis tool that offers a combination of data visualization, data processing and search functionality that improves the speed and ease with which researchers can analyze, access and visualize structural data of DNA-protein complexes. In this paper, we report significant improvements made to DNAproDB since its initial release. DNAproDB now supports any DNA secondary structure from typical B-form DNA to single-stranded DNA to G-quadruplexes. We have updated the structure of our data files to support complex DNA conformations, multiple DNA-protein complexes within a DNAproDB entry and model indexing for analysis of ensemble data. Support for chemically modified residues and nucleotides has been significantly improved along with the addition of new structural features, improved structural moiety assignment and use of more sequence-based annotations. We have redesigned our report pages and search forms to support these enhancements, and the DNAproDB website has been improved to be more responsive and user-friendly. DNAproDB is now integrated with the Nucleic Acid Database, and we have increased our coverage of available Protein Data Bank entries. Our database now contains 95% of all available DNA-protein complexes, making our tools for analysis of these structures accessible to a broad community.

Federating Structural Models and Data: Outcomes from A Workshop on Archiving Integrative Structures.

Structures of biomolecular systems are increasingly computed by integrative modeling. In this approach, a structural model is constructed by combining information from multiple sources, including varied experimental methods and prior models. In 2019, a Workshop was held as a Biophysical Society Satellite Meeting to assess progress and discuss further requirements for archiving integrative structures. The primary goal of the Workshop was to build consensus for addressing the challenges involved in creating common data standards, building methods for federated data exchange, and developing mechanisms for validating integrative structures. The summary of the Workshop and the recommendations that emerged are presented here.