Pharm201 Lecture Data Representation Pharm 201/Bioinformatics I Philip E. Bourne Department of Pharmacology, UCSD Prerequisite Reading: Structural Bioinformatics Chapters 10

Pharm201 Lecture Take Home Message Good data representation of complex data is not a trivial undertaking However it is prerequisite to effective use of those data History often precludes the above You should have got a sense of the first item from the assignment

Pharm201 Lecture Global Considerations in Defining a Data Representation Scope - breadth and depth of data to be included Name space How to cast that data What will the definition be used for? – Archiving, schema representation, methods...

Pharm201 Lecture  Simple query, browsing and retrieval  Consistent data resulting from autonomous validation and verification  Simple and consistent data exchange  A unified view of disparate types of data  Accommodation of new knowledge as it is discovered  Inclusion of procedures (methods) to specify how a particular item of data is derived or verified. Global Considerations – More Specifically

Pharm201 Lecture Given These Considerations – Where Does the PDB Format Fit In? First we need to examine the format

Pharm201 Lecture The PDB Format A full description is at It was designed around an 80 column punched card! It was designed to be human readable It is used by every piece of software that deals with structural data

Pharm201 Lecture The PDB Format – An Example – The Header

Pharm201 Lecture The PDB Format - Records Every PDB file may be broken into a number of lines terminated by an end-of-line indicator. Each line in the PDB entry file consists of 80 columns. The last character in each PDB entry should be an end-of-line indicator. Each line in the PDB file is self-identifying. The first six columns of every line contain a record name, left-justified and blank-filled. This must be an exact match to one of the stated record names. The PDB file may also be viewed as a collection of record types. Each record type consists of one or more lines. Each record type is further divided into fields.

Pharm201 Lecture The PDB Format – An Example – The Atomic Coordinates

Pharm201 Lecture The Description – Atom Records

Pharm201 Lecture What is Wrong with this Approach? The description and the data are separate Parsing is a nightmare – the most complex piece of code we have in our research laboratory probably remains the PDB parser There are no relationships between items of data Some data just cannot be parsed ….

Pharm201 Lecture REMARK 3 REFINEMENT. BY THE RESTRAINED LEAST-SQUARES PROCEDURE OF REMARK 3 J. KONNERT AND W. HENDRICKSON (PROGRAM *PROLSQ*). THE R REMARK 3 VALUE IS FOR 2680 REFLECTIONS WITH I GREATER THAN REMARK 3 2.0*SIGMA(I) REPRESENTING 74 PER CENT OF THE TOTAL REMARK 3 AVAILABLE DATA IN THE RESOLUTION RANGE 10.0 TO 2.0 REMARK 3 ANGSTROMS. REMARK 4 THE ERABUTOXIN A (EA) CRYSTAL STRUCTURE IS ISOMORPHOUS WITH REMARK 4 THE KNOWN STRUCTURE OF ERABUTOXIN B (PROTEIN DATA BANK REMARK 4 ENTRIES *2EBX*, *3EBX*). EA DIFFERS FROM EB BY A SINGLE REMARK 4 SUBSTITUTION - EA ASN 26 FOR EB HIS 26. THE EA STARTING REMARK 4 MODEL WAS OBTAINED FROM A MOLECULAR REPLACEMENT STUDY IN REMARK 4 WHICH COORDINATES FOR 309 OF THE 475 ATOMS IN THE EB REMARK 4 STRUCTURE (*2EBX*) WERE USED. PDB Format - Important Components of the Data are Lost to All But Humans

Pharm201 Lecture Enter mmCIF Prerequisite reading: Complete information:

Pharm201 Lecture The macromolecular Crystallographic Information File (mmCIF) – An Approach to Addressing Problems with the PDB Format Has the support of a major scientific society In the backbone of the current PDB Provides a rich description of very complex data Predates any use of ontologies, Web developments, CORBA, XML etc. Still has some problems

Pharm201 Lecture The temperature is 30 degrees A human would know whether that was Centigrade or Fahrenheit with additional context. A computer would have more difficulty! What would be the point of archiving such data if in 10 years the meaning was lost mmCIF - Initial Motivator Circa Late 1980’s

Pharm201 Lecture All PDB data should be captured Describe a paper’s material and methods section Describe biologically active molecule Fully describe secondary structure but not tertiary or quaternary Describe details of chemistry (inc. 2D) Meaningful 3D views mmCIF – Scope of the Initial Effort

Pharm201 Lecture mmCIF - Topology

Pharm201 Lecture Data are defined in data blocks A global declaration spans data blocks Data exists as name-value pairs A data name may appear only once in a data block Loop constructs are supported mmCIF - STAR Encoding Rules

Pharm201 Lecture loop_ _atom_site.group_PDB _atom_site.type_symbol _atom_site.label_atom_id _atom_site.label_comp_id _atom_site.label_asym_id _atom_site.label_seq_id _atom_site.label_alt_id _atom_site.Cartn_x _atom_site.Cartn_y _atom_site.Cartn_z _atom_site.occupancy _atom_site.B_iso_or_equiv _atom_site.footnote_id _atom_site.entity_id _atom_site.entity_seq_num _atom_site.id ATOM N N VAL A ATOM C CA VAL A ATOM C C VAL A mmCIF - Extract from a Data File

Pharm201 Lecture save__atom_site.Cartn_x _item_description.description ; The x atom site coordinate in angstroms specified according to a set of orthogonal Cartesian axes related to the cell axes as specified by the description given in _atom_sites.Cartn_transform_axes. ; _item.name '_atom_site.Cartn_x' _item.category_id atom_site _item.mandatory_code no _item_aliases.alias_name '_atom_site_Cartn_x' _item_aliases.dictionary cifdic.c94 _item_aliases.version 2.0 loop_ _item_dependent.dependent_name '_atom_site.Cartn_y' '_atom_site.Cartn_z' _item_related.related_name '_atom_site.Cartn_x_esd' _item_related.function_code associated_esd _item_sub_category.id cartesian_coordinate _item_type.code float _item_type_conditions.code esd _item_units.code angstroms mmCIF - Extract from the Dictionary

Pharm201 Lecture The DDL category item_description holds a description for each data item. The key item for this category is item_description.name which is defined in the parent category item. The text of the item description is held by item _item_description.description. A single description may be provided for each data item. The DDL for the item_description category is given in the following section. save_ITEM_DESCRIPTION _category.description ; This category holds the descriptions of each data item. ; _category.id item_description _category.mandatory_code yes loop_ _category_key.name '_item_description.name' '_item_description.description' loop_ _category_group.id 'ddl_group' 'item_group' save_ save__item_description.description _item_description.description ; Text decription of the defined data item. ; _item.name '_item_description.description' _item.category_id item_description _item.mandatory_code yes _item_type.code text save_ mmCIF Dictionary Definition Language

Pharm201 Lecture mmCIF – Topology Revisited

Pharm201 Lecture STRUCT_BIOL STRUCT_BIOL_GEN STRUCT_ASYM ENTITY ENTITY_POLY ENTITY_POLY_SEQ CHEM_COMP ATOM_SITE STRUCT_CONF STRUCT_CONN STRUCT_SITE_GEN STRUCT_REF mmCIF - The Category Group Organization of any Macromolecular Structure

Pharm201 Lecture mmCIF - Entity - Unique Chemical Component

25

26 Entity Information

Pharm201 Lecture STRUCT_BIOL STRUCT_BIOL_GEN STRUCT_ASYM ENTITY ENTITY_POLY ENTITY_POLY_SEQ CHEM_COMP ATOM_SITE STRUCT_CONF STRUCT_CONN STRUCT_SITE_GEN STRUCT_REF mmCIF - The Category Group Organization of any Macromolecular Structure

28 Shows ATOM and UniProt Sequences

Pharm201 Lecture STRUCT_BIOL STRUCT_BIOL_GEN STRUCT_ASYM ENTITY ENTITY_POLY ENTITY_POLY_SEQ CHEM_COMP ATOM_SITE STRUCT_CONF STRUCT_CONN STRUCT_SITE_GEN STRUCT_REF mmCIF - The Category Group Organization of any Macromolecular Structure

Pharm201 Lecture STRUCT_BIOL STRUCT_BIOL_GEN STRUCT_ASYM ENTITY ENTITY_POLY ENTITY_POLY_SEQ CHEM_COMP ATOM_SITE STRUCT_CONF STRUCT_CONN STRUCT_SITE_GEN STRUCT_REF mmCIF - The Category Group Organization of any Macromolecular Structure

Pharm201 Lecture STRUCT_BIOL STRUCT_BIOL_GEN STRUCT_ASYM ENTITY ENTITY_POLY ENTITY_POLY_SEQ CHEM_COMP ATOM_SITE STRUCT_CONF STRUCT_CONN STRUCT_SITE_GEN STRUCT_REF mmCIF - The Category Group Organization of any Macromolecular Structure

Pharm201 Lecture STRUCT_BIOL STRUCT_BIOL_GEN STRUCT_ASYM ENTITY ENTITY_POLY ENTITY_POLY_SEQ CHEM_COMP ATOM_SITE STRUCT_CONF STRUCT_CONN STRUCT_SITE_GEN STRUCT_REF mmCIF - The Category Group Organization of any Macromolecular Structure

Pharm201 Lecture STRUCT_BIOL STRUCT_BIOL_GEN STRUCT_ASYM ENTITY ENTITY_POLY ENTITY_POLY_SEQ CHEM_COMP ATOM_SITE STRUCT_CONF STRUCT_CONN STRUCT_SITE_GEN STRUCT_REF mmCIF - The Category Group Organization of any Macromolecular Structure

Pharm201 Lecture STRUCT_BIOL STRUCT_BIOL_GEN STRUCT_ASYM ENTITY ENTITY_POLY ENTITY_POLY_SEQ CHEM_COMP ATOM_SITE STRUCT_CONF STRUCT_CONN STRUCT_SITE_GEN STRUCT_REF mmCIF - The Category Group Organization of any Macromolecular Structure

mmCIF - Defining Secondary Structure 35

mmCIF - Other Interactions 36Pharm201 Lecture

mmCIF – Defining the Biological Assembly Pharm201 Lecture _pdbx_struct_assembly.id 1 _pdbx_struct_assembly.details author_and_software_defined_assembly _pdbx_struct_assembly.method_details PISA _pdbx_struct_assembly.oligomeric_details dimeric _pdbx_struct_assembly.oligomeric_count 2 # _pdbx_struct_assembly_gen.assembly_id 1 _pdbx_struct_assembly_gen.oper_expression 1,2 _pdbx_struct_assembly_gen.asym_id_list A,B,C,D,E,F,G,H loop_ _pdbx_struct_oper_list.id _pdbx_struct_oper_list.type _pdbx_struct_oper_list.name _pdbx_struct_oper_list.symmetry_operation _pdbx_struct_oper_list.matrix[1][1] _pdbx_struct_oper_list.matrix[1][2] _pdbx_struct_oper_list.matrix[1][3] _pdbx_struct_oper_list.vector[1] _pdbx_struct_oper_list.matrix[2][1] _pdbx_struct_oper_list.matrix[2][2] _pdbx_struct_oper_list.matrix[2][3] _pdbx_struct_oper_list.vector[2] _pdbx_struct_oper_list.matrix[3][1] _pdbx_struct_oper_list.matrix[3][2] _pdbx_struct_oper_list.matrix[3][3] _pdbx_struct_oper_list.vector[3] 1 'identity operation' 1_555 x,y,z 'crystal symmetry operation' 4_565 x,-y+1,-z Asymmetric Unit (monomer) Biological Assembly (dimer) The pdbx_struct_assembly category describes the components and symmetry operators required to generate the biological assembly The pdbx_struct_oper category describes the symmetry operations. Each symmetry operation consists of a 3x3 rotation matrix and a translation vector. Example: PDB 3C70

Pharm201 Lecture mmCIF – Defining non-standard Amino Acids

Pharm201 Lecture mmCIF - Problems Two sets of chain identifier and residue numbering schemes (cif and author defined) –Example: _atom_site.label_asym_id, _atom_site.author_asym_id –PDB files use the author defined scheme Poor data typing Redundant or unnecessary data (i.e. amino acid info) Use of free text instead of controlled vocabulary – IMAGE PLATE (RAXIS V) IMAGE PLATE (RAXIS-V) IMAGE PLATE RAXIS V IMAGE PLATE RAXIS-V RAXISIV Little software support due to complexity of mmCIF format Parsing issues

Examples of File Parsing Issues Non-standard quoting rules for strings Items that require sub-parsing of expressions Pharm201 Lecture loop_ _pdbx_struct_assembly_gen.assembly_id _pdbx_struct_assembly_gen.oper_expression _pdbx_struct_assembly_gen.asym_id_list 1 '(1-60)(61-88)' A,B,C 4 '(1,2,6,10,23,24)(61-88)' A,B,C 6 '(1,10,23)(61,62,69-88)' A,B,C PAU '(P)(61-88)' A,B,C TURN_P TURN_P1 'A'"' VAL A 31 ? ILE A 34 ? VAL A 31 ILE A 34 ? ;TYPE I' ; ?

Pharm201 Lecture Summary mmCIF has provided the PDB with a robust data representation which serves as conceptual and physical schema upon which the current RCSB, PDBe and PDBj are built This work predated XML and XML-schema but embodies the important concepts inherent in these descriptions mmCIF was later exactly converted into XML and is now used more than mmCIF, but much less than the old PDB format

Pharm201 Lecture Take Home Message Good data representation of complex data is not a trivial undertaking However it is prerequisite to effective use of those data