SetupMetalsMover

Documentation and mover by Sharon Guffy (guffy@email.unc.edu). Original -auto_setup_metals functionality, and note on scoring, added by Vikram K. Mulligan (vmullig@uw.edu).

Table of Contents

- SetupMetalsMover

Description

This mover replicates the function of the -in:auto_setup_metals command line flag in mover form. "Setting up" a metal ion entails adding covalent bonds between the ion and all bound atoms (detected as metal binding atoms within a distance determined by the Lennard Jones radii of the two atoms) and adding distance, angle, and coordinate constraints between the metal ion and the coordinating atoms. In the process, new variant types are also added to the metal ion and all coordinating residues. By default, all metal ions are set up; the user can specify a residue selector (as a subtag or previously defined selector), which restricts setup to only metal ions contained within the selection.

Note regarding scoring

The SetupMetalsMover has two effects on scoring. First, by creating bonds between a metal and metal-coordinating residues, the mover tells the scorefunction not to calculate repulsive and long-range interactions between the metal and the atoms that coordinate it. Without this, Rosetta scores a structure containing a metal as though there is a clash between the metal and the atoms coordinating it. Second, by adding constraints between the metal and the coordinating atoms, Rosetta will penalize deviations from the input metal-coordination geometry during scoring, and will "pull" the geometry towards the input coordination geometry during relaxation (minimization). Without this, the metal centre is likely to become distorted during minimization or other structural manipulation. Note that the second effect requires that the metalbinding_constraint score term is active in the scorefunction used to score or energy-minimize. If necessary, this can be achieved by adding it to the weights file, or by using the Reweight command in RosettaScripts (see the ScoreFunctions section of this page for details).

Note on centroid mode compatibility

The covalent attachments and constraints enabled by this mover should be compatible with centroid mode, with a few caveats. As sidechain atoms are normally missing from centroid mode, residues which are coordinated to metals through sidechain atoms are treated specially. Specifically, a special centroid mode residue type which contains explicit sidechain atoms will be created. As it is not a standard centroid mode type, it will not necessarily be scored equivalently to a non-conjugated residue. Additionally, as centroid mode protocols typically don't sample sidechain flexibility, the sidechain conformation will effectively be "locked" in the starting conformation. While this should work when sampling away from the metal ions, sampling in the vicinity of the metal binding residues may be biased due to the comparative inflexibility of the sidechain/metalbinding geometry.

Setup and options

<SetupMetalsMover name="(&string)" metals_detection_LJ_multiplier="(&Real 1.0)" 
  metals_distance_constraint_multiplier="(&Real 1.0)" metals_angle_constraint_multiplier="(&Real 1.0)"
  remove_hydrogens="(&bool true)" resnums="(&nonnegative_int_cslist)" metal_residue_selector="(&string)" constraints_only="(&bool false)" >
         <Optional residue selector subtag />
</SetupMetalsMover>

Note that the resnums option, the residue_selector option, and the residue selector subtag are mutually exclusive. Only one selector OR a resnum list may be provided.

metals_detection_LJ_multiplier: A multiplier used to increase or decrease the detection radius for metal binding atoms. Setting this value too high may result in false positives in contact detection and can lead to errors due to the detection of more contacts than the metal can bind. If this is not set in the mover tag, it uses the value set through the command line (default 1.0).
metals_distance_constraint_multiplier: Multiplier for the weight of the distance constraints between the metal ion and its coordinating atoms. Increasing this weight will make the binding site more rigid; it can be set to zero to turn off distance constraints. If this is not set in the mover tag, it uses the value set through the command line (default 1.0).
metals_angle_constraint_multiplier: Multiplier for the weight of the angle constraints about metal coordinating atoms (metal-ligand-ligand_base). Increasing this weight will make the binding site more rigid; it can be set to zero to turn off angle constraints. If this is not set in the mover tag, it uses the value set through the command line (default 1.0).
remove_hydrogens: Should extraneous hydrogens be removed from metal binding atoms? Default true.
resnums: Comma-separated list of residue numbers (can include ranges e.g. 1-10) specifying where to search for metal ions to set up. Mutually exclusive with residue selectors.
metal_residue_selector: Name of previously defined residue selector specifying which metal ions to set up. Mutually exclusive with resnums and residue selector subtags.
constraints_only: Only add constraints and do not set up covalent bonds/variant types. Useful for restoring constraints added by metal setup after they have been deleted.

Autogenerated Tag Syntax Documentation:

Mover that adds chemical bonds and distance/angle constraints between metal ions and their coordinating atoms. If a residue selector or resnum list are provided, only sets up the specified metals. Otherwise, sets up all metals.

References and author information for the SetupMetalsMover mover:

SetupMetalsMover Mover's citation(s): Mulligan VK, Workman S, Sun T, Rettie S, Li X, Worrall LJ, Craven TW, King DT, Hosseinzadeh P, Watkins AM, Renfrew PD, Guffy S, Labonte JW, Moretti R, Bonneau R, Strynadka NCJ, and Baker D. (2021). Computationally designed peptide macrocycle inhibitors of New Delhi metallo-β-lactamase 1. Proc Natl Acad Sci USA 118(12). doi: 10.1073/pnas.2012800118.

<SetupMetalsMover name="(&string;)" remove_hydrogens="(true &bool;)"
        constraints_only="(false &bool;)" add_constraints="(true &bool;)"
        metals_detection_LJ_multiplier="(1.0 &real;)"
        metals_distance_constraint_multiplier="(1.0 &real;)"
        metals_angle_constraint_multiplier="(1.0 &real;)"
        metal_residue_selector="(&string;)"
        contact_residue_selector="(&string;)"
        metal_resnums="(&resnum_list_with_ranges;)"
        contact_resnums="(&resnum_list_with_ranges;)" />

remove_hydrogens: Should hydrogens on metal binding atoms be removed?
constraints_only: Should we ONLY add the constraints to the metal and not set up covalent bonds? Useful for repeated applications of the mover if constraints are deleted.
add_constraints: Should we add constraints to the pose? May be used if, for example, the user wants to add their own custom constraints elsewhere.
metals_detection_LJ_multiplier: Multiplier for the distance cutoff for contact detection, which is based on the Lennard-Jones radii of the two atoms. This option overrides default value set through the command line.
metals_distance_constraint_multiplier: Multiplier for distance constraints between metal and metal-binding atoms. This option overrides default value set through the command line.
metals_angle_constraint_multiplier: Multiplier for angle constraints between metal and metal-binding atoms. This option overrides default value set through the command line.
metal_residue_selector: Selector used to indicate which metal residues should be set up. If no selector or resnum string is provided, all metals will be set up. The name of a previously declared residue selector or a logical expression of AND, NOT (!), OR, parentheses, and the names of previously declared residue selectors. Any capitalization of AND, NOT, and OR is accepted. An exclamation mark can be used instead of NOT. Boolean operators have their traditional priorities: NOT then AND then OR. For example, if selectors s1, s2, and s3 have been declared, you could write: 's1 or s2 and not s3' which would select a particular residue if that residue were selected by s1 or if it were selected by s2 but not by s3.
contact_residue_selector: Selector used to indicate which metal contacts should be set up. If no selector or resnum string is provided, all contacts for the specified metals will be set up. The name of a previously declared residue selector or a logical expression of AND, NOT (!), OR, parentheses, and the names of previously declared residue selectors. Any capitalization of AND, NOT, and OR is accepted. An exclamation mark can be used instead of NOT. Boolean operators have their traditional priorities: NOT then AND then OR. For example, if selectors s1, s2, and s3 have been declared, you could write: 's1 or s2 and not s3' which would select a particular residue if that residue were selected by s1 or if it were selected by s2 but not by s3.
metal_resnums: List of residue numbers to use
contact_resnums: List of residue numbers to use

Example

The following script applies metal-binding constraints to the input pose, then relaxes it using the FastRelax mover:

<ROSETTASCRIPTS>
        <SCOREFXNS>
                <ScoreFunction name="r15_cst" weights="ref2015_cst.wts" >
                        <Reweight scoretype="metalbinding_constraint" weight="1.0" />
                </ScoreFunction>
        </SCOREFXNS>
        <MOVERS>
                <SetupMetalsMover name="setup_metals" metals_detection_LJ_multiplier="1.0" />
                <FastRelax name="frlx1" scorefxn="r15_cst" />
        </MOVERS>
        <PROTOCOLS>
                <Add mover="setup_metals" />
                <Add mover="frlx1" />
        </PROTOCOLS>
</ROSETTASCRIPTS>

Removing metal bonds and constraints

The RemoveMetalConnectionsMover may be used to remove the bonds and variant types added with this mover. The ClearConstraintsMover in turn may be used to remove the constraints added with this mover.

SetupMetalsMover