Ligands, dictionary and refinement
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Ligands, dictionary and refinement Garib N Murshudov York Structural Biology Laboratory University of York. Outline. Introduction Dictionary of ligands Sources of dictionary and idealised coordinates Tools for ligand description in ccp4 How to use dictionary in refinement (REFMAC)

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Outline 4611186

Ligands, dictionary and refinementGarib N MurshudovYork Structural Biology LaboratoryUniversity of York


Outline

Outline

  • Introduction

  • Dictionary of ligands

  • Sources of dictionary and idealised coordinates

  • Tools for ligand description in ccp4

  • How to use dictionary in refinement (REFMAC)

  • Conclusions


The need for prior chemical knowledge

The need for prior chemical knowledge

  • Refinement

  • Atomic model description

Graphics

Simulations

………..


Atomic model description

Atomic model description

Default pointers in PDB file

. . . . . .ATOM 7 C LEU A 5 37.584 4.085 ATOM 8 O LEU A 5 36.548 3.447 ATOM 9 N ILE A 6 37.887 5.098 ATOM 10 CA ILE A 6 37.032 5.447 ATOM 11 CB ILE A 6 37.835 6.276 . . . . . .

Pointer to link description

Pointer to monomer description

Pointer to atom description


Refmac5 dictionary

Refmac5 Dictionary

  • Describes all amino acids

  • All nucleic acids

  • Common sugars

  • Many organic and inorganic compounds

  • Links and modifications

    There are tools to deal with dictionary

    Dictionary format is mmCIF


General category

General category

data_comp_listloop__chem_comp.id_chem_comp.three_letter_code_chem_comp.name_chem_comp.group_chem_comp.number_atoms_all_chem_comp.number_atoms_nh_chem_comp.desc_level. . . . . . . . . GLC-b-D GLC 'beta_D_glucose ' D-pyranose 24 12 .

Group: peptide, DNA/RNA, pyranose, non-polymer

Level: C or M – complete or minimal description


Atom category

Atom category

loop__chem_comp_atom.comp_id_chem_comp_atom.atom_id_chem_comp_atom.type_symbol_chem_comp_atom.type_energy_chem_comp_atom.partial_charge_chem_comp_atom.x_chem_comp_atom.y_chem_comp_atom.z

GLC-b-D C1 C CH1 0 0.0 0.0 0.0

GLC-b-D H1 H HCH1 0 0.522 -0.087 0.801

. . . . .


Bond category

Bond category

loop__chem_comp_bond.comp_id_chem_comp_bond.atom_id_1_chem_comp_bond.atom_id_2_chem_comp_bond.type_chem_comp_bond.value_dist_chem_comp_bond.value_dist_esd GLC-b-D O1 C1 single 1.410 0.020 GLC-b-D C2 C1 single 1.524 0.020 . . . . .

Type: single, double, triple, aromatic, metal


Angle category

Angle category

loop__chem_comp_angle.comp_id_chem_comp_angle.atom_id_1_chem_comp_angle.atom_id_2_chem_comp_angle.atom_id_3_chem_comp_angle.value_angle_chem_comp_angle.value_angle_esd GLC-b-D H1 C1 O1 109.470 3.000 GLC-b-D O1 C1 C2 109.470 3.000. . . . . .


Torsion angles category

Torsion angles category

loop__chem_comp_tor.comp_id_chem_comp_tor.id_chem_comp_tor.atom_id_1_chem_comp_tor.atom_id_2_chem_comp_tor.atom_id_3_chem_comp_tor.atom_id_4_chem_comp_tor.value_angle_chem_comp_tor.value_angle_esd_chem_comp_tor.period GLC-b-D var_1 C1 C2 O2 HO2 0.000 20.000 1 GLC-b-D var_2 C1 C2 C3 C4 -50.095 20.000 3. . . . . .

1

4

2

3

Period: number of energetic minima


Chirality category

Chirality category

1.Tetrahedral chirality

Usually on C or N

with sp3 hybridisation

2.Non-tetrahedral chirality

Usually for metal

coordination


Chirality category1

Chirality category

loop__chem_comp_chir.comp_id_chem_comp_chir.id_chem_comp_chir.atom_id_centre_chem_comp_chir.atom_id_1_chem_comp_chir.atom_id_2_chem_comp_chir.atom_id_3_chem_comp_chir.volume_signGLC-b-D chir_01 C5 C4 O5 C6 positiveGLC-b-D chir_02 C4 C3 O4 C5 positive GLC-b-D chir_03 C3 C2 O3 C4 negative GLC-b-D chir_04 C2 C1 O2 C3 positive

. . . . .

1

3

C

_

Sign: positive, negative, both, anomer

+


Metal chirality

Metal chirality is only used to create coordinates

loop__chem_comp_chir.comp_id_chem_comp_chir.id_chem_comp_chir.atom_id_centre_chem_comp_chir.atom_id_1_chem_comp_chir.atom_id_2. . . . _chem_comp_chir.atom_id_8_chem_comp_chir.volume_signMONid chir_id Ac Ab Af A1 A2 A3 A4 A5 A6 cross6Where: Ac - chiral centre atom Ab - back atom,Af - forward atom A1,A2,...,AN - atoms in the same plane, N can be = 0,1,2,3,4,5,6 these atoms form the point group. crossN - cross chirality specification

Metal chirality


Example metal chirality oc7

Example metal chirality (OC7)

OC7 chir_01 CA O5 O7 O1 O4 O2 O3 O6 . cross5

O1

O4

O6

O5

O7

CA

O3

O2


Plane category

Plane category

loop__chem_comp_plane_atom.comp_id_chem_comp_plane_atom.plane_id_chem_comp_plane_atom.atom_id_chem_comp_plane_atom.dist_esd PHE plan CB 0.020 PHE plan CG 0.020 PHE plan CD1 0.020 . . . . .


Example of a modification

Example of a modification

Modification formalism allows to change a monomer

Modification describes in details the result of chemical reaction


Modification general category

Modification: general category

data_mod_listloop__chem_mod.id_chem_mod.name_chem_mod.comp_id_chem_mod.group_id. . . . . . O1MET O1_metyl_of_sugar . pyranose

group_id: means only for sugars


Modification atom category

Modification: atom category

loop__chem_mod_atom.mod_id_chem_mod_atom.function_chem_mod_atom.atom_id_chem_mod_atom.new_atom_id_chem_mod_atom.new_type_symbol_chem_mod_atom.new_type_energy_chem_mod_atom.new_partial_charge O1MET change O1 . . O2 0.000 O1MET delete HO1 . . . 0.000 O1MET add . CM C CH3 0.000 O1MET add . HM1 H HCH 0.000 . . . . . .

function: only - change, delete or add


Modification bond category

Modification: bond category

loop__chem_mod_bond.mod_id_chem_mod_bond.function_chem_mod_bond.atom_id_1_chem_mod_bond.atom_id_2_chem_mod_bond.new_type_chem_mod_bond.new_value_dist_chem_mod_bond.new_value_dist_esd O1MET add O1 CM single 1.420 0.020 O1MET add CM HM1 single 0.960 0.020 O1MET add CM HM2 single 0.960 0.020 O1MET add CM HM3 single 0.960 0.020


Example of peptide link

Example of peptide link

Link formalism allows to join monomers together

Link describes in details the result of chemical reaction


Link general category

Link: general category

data_link_listloop__chem_link.id_chem_link.comp_id_1_chem_link.mod_id_1_chem_link.group_comp_1_chem_link.comp_id_2_chem_link.mod_id_2_chem_link.group_comp_2_chem_link.nameALPHA1-4 . DEL-HO4 pyranose . DEL-O1 pyranose

glycosidic_bond_alpha1-4

mod_id _1: modification of first monomer before the linkage

mod_id_2 : modification of second monomer before the linkage


Link bond category

Link: bond category

loop__chem_link_bond.link_id_chem_link_bond.atom_1_comp_id_chem_link_bond.atom_id_1_chem_link_bond.atom_2_comp_id_chem_link_bond.atom_id_2_chem_link_bond.type_chem_link_bond.value_dist_chem_link_bond.value_dist_esd ALPHA1-4 1 O4 2 C1 single 1.439 0.020

atom_1_comp_id: means first monomer

atom_2_comp_id: means second monomer


Source of dictionary and coordinates

Source of dictionary and coordinates

  • MSDchem

  • PRODRG

  • RELIBASE

  • CORINA

  • QM or other energy minimsation programs

  • CSD


Msdchem

MSDchem

You can search by formula, substructure and others. Results can be

save as cif file and used by libcheck to create dictionary for refmac


Msdchem jme

MSDchem: JME

1) Draw substructure,

write a smile file or

load SDF, MOL, mmCIF,

2) Search


Prodrg server

PRODRG server

JME

Load your file


Prodrg jme

PRODRG: JME

Draw your ligand,

transfer to PRODRG

window and run


Prodrg output

PRODRG output

It can write out

dictionaries for CNS

REFMAC5, SHELX

and others


Tools in ccp4

Tools in CCP4

LIBCHECK - creates the complete monomer description

from minimal

- creates coordinates from complete monomer

description

SKETCHER - graphical program that creates the minimal

monomer description for LIBCHECK

MAKECIF - creates restraints


Ways to create dictionary

Ways to create dictionary

1. From chemical structure

Using SKETCHER: monomer is drawn specifying

atoms and bonds

From SMILE strings, sdf file, mol2 file

2. From Cartesian coordinates

Coordinates from CSD

Energetically optimised coordinates

MOL2 file

SDF file


Smile strings an example

Smile strings: An example

SMILE for ALA:

N[C@@H](C)C(=O)O

3D representation:

For description of smile:

http://www.daylight.com/dayhtml_tutorials/languages/smiles/index.html


Sketcher

Sketcher

Initial 2D sketch

After LIBCHECK and

REFMAC


Restraints monomer linkage

Restraints:monomer linkage

  • Chain links (trans/cis, DNA/RNA, sugar links, gap)

  • Standard links (SS bridges, sugar-protein links)

  • Potential links

  • Links between alternative conformations

  • Symmetry links

  • User links


Modifications and links in pdb file

Modifications and links in PDB file

Link ID

SSBOND 1 CYS L 88 CYS L 23LINK SG CYS H 195 2.031 SG BCYS H 140 SSLINK TYR L 139 PRO L 140 PCISLINK GLY H 127 GLY H 133 gapLINK MAG Y 1 GAL Y 2 BETA1-4LINK O LEU B 61 NA NA X 6 LEU-NALINK OE1 GLU A 139 NA NA X 1 12555 symmetry

Standard name

Modification ID

Name in PDB file

MODRES GAL Y 2 GAL-b-D RENAME


Conclusions

Conclusions

  • Ligand dictionaries should designed with care. Interpetation of chemistry may depend on that

  • Such resources as MSDchem, PRODRG can help to create an accurate dictionary

  • Links and modifications are important component for understanding protein chemistry

  • Unfortunately no automatic link generation programs available yet (we are working on that)


Acknowledgments

Acknowledgments

  • Alexei Vagin – YSBL, York

  • Roberto Steiner – Kings coll.

  • Andrey Lebedev – YSBL, York

  • Liz Potterton – YSBL, York

  • Fei Long – YSBL, York

  • Wellcome Trust, BBSRC, BIOXHIT, CCP4 – money


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