Authors: Nir London, Barak Raveh, Dana Movshovitz-Attias, Yuval Sadan, Orly Marcu, Ora Schueler-Furman
The documentation was last updated on Aug 19, 2018, by Orly Marcu. Questions about this documentation should be directed to Ora Furman: (firstname.lastname@example.org).
The PeptiDerive app may be found under
apps/public/analysis/PeptideDeriver.cc. It uses JD2 to invoke the
PeptideDeriverFilter class, defined in
A unit test for this application is in
PeptiDerive also comes as a RosettaScripts Filter flavor.
Original work published as:
London N., Raveh B., Movshovitz-Attias D., Schueler-Furman O. (2010) "Can self-inhibitory peptides be derived from the interfaces of globular protein-protein interactions?", Proteins. V 78, pp 3140–9.
Paper about ROSIE based server:
Sedan Y., Marcu O., Lyskov S., Schueler-Furman O. (2016) "Peptiderive server: derive peptide inhibitors from protein–protein interactions", NAR V 44(Web Server issue), pp W536–W541.
PeptiDerive is a simple application that derives from a given interface the linear stretch that contributes most of the binding energy (approximated as the score over the interface). In a sense, it is the computational analog of a peptide micro-array, as it scans different possible peptides extracted from a protein in its interactions with its partners. This protocol has been extended to detect and model cyclic peptides (closed either by forming a disulfide bond or a peptide bond between its termini) that can be generated from a given interface.
A previous run of this protocol on two highly reliable benchmarks showed that the fraction of interfaces that could potentially be inhibited by a peptide or a peptidomimetic amounts to around 50% of the tested interactions. Further simulations with FlexPepDock of some of the derived peptides indicate that they will assume a similar conformation when cut out to the conformation they adopt within the full protein. This does not really look at conformational entropy, it just evaluates the local stability (London, Raveh, Movshovitz-Attias & Schueler-Furman (2010). Can self-inhibitory peptides be derived from the interfaces of globular protein-protein interactions? Proteins, 78:314. doi:10.1002/prot.22785). Also, PeptiDerive analysis of a set of solved complex structures, where there are also solved structures of small molecules bound to one of the partners indicates that these target the same sites as identified by this simple protocol (the molecules come from in vitro screens, not drug design of course) (London, Raveh & Schueler-Furman (2013). Druggable protein–protein interactions—from hot spots to hot segments. Current Opinion in Chemical Biology. doi:10.1016/j.cbpa.2013.10.011)
PeptiDerive uses a simple protocol for the selection and evaluation of protein-protein interface-derived peptides. Given the complex structure of an interaction between proteins A and B, a short minimization of the structure is performed using the Rosetta energy function to remove local clashes without changing the structure significantly. Then, a sliding window of amino acids, the length of which is determined by the user (e.g. a window of 10 amino acids), slides along the protein chain. Each fragment of the determined length is extracted from its protein context, termini charges are added, and then the interaction energy of this peptide with the other partner is estimated. The peptide that contributes the best interaction energy is selected to represent this interaction (the peptide can be located in either of the two protein partners).
A coarse estimate of binding energy is provided by evaluating the interface energy, defined as the energy of a peptide in complex with the protein partner compared with the energy of peptide and protein alone. The binding energy for a peptide derived from protein A to receptor protein B is calculated as
The peptide that contributes the best ΔΔGApepB value is selected to represent this interaction. The relative contribution of this peptide to the total binding energy is obtained by comparing its binding energy to the estimated binding energy of the full protein complex,
This rough estimate is used for filtering of candidate inhibitory peptides.
For each of those peptides which contribute significantly to binding energy (user defined; default: over 35% of the interface score), generation of a cyclic peptide is performed on-the-fly, by either formation of a disulfide bond or of a peptide bond. If the distance between the flanking residues of the peptide (those immediately before and after the segment of interest) is reasonable for the formation of a disulfide bond (i.e., C𝛽 atoms within 3-5Å, or C𝛂 atoms within 4.5-6.5Å for Glycine/s) and the two residue's geometry fits that of known disulfide-forming structures (as evaluated by a Rosetta disulfide potential match score), the protocol next mutates the residues adjacent to the loop to cysteines, forms a disulfide bridge, performs a minimization of the peptide backbone to form an optimized disulfide bond and re-evaluates the energy gain by disulfide bond formation and the binding energy of the new cyclic-peptide to its partner. Only peptides with a change in disulfide bond energy of up to 1 Rosetta Energy Unit (REU) upon cyclization are reported (with this option accessible to user based changes via the -max_dslf_energy flag). In parallel, For each peptide, the distance between the nitrogen atom of the N-terminal residue and the carbon of the C-terminal residue is calculated, and peptides with N-to-C distances up to 5Å are retained as candidates for cyclization via head-to-tail cyclization. The cyclized peptide backbone undergoes minimization, followed by re-evaluation of the binding energy of the new cyclic-peptide to its partner. These perturbations are performed by the PeptideCyclizeMover Cyclic peptides are accepted and outputted only if the estimated binding energy of the cyclic peptide is negative.
The program expects a multi-chain PDB file.
To avoid parsing problems, make sure your PDB file is made up of only
TER records, i.e. no heteroatoms (HETATM) are included, and that the occupancy column is filled (no double conformations or 0.00 occupancy).
To use phosphorylated residues, make sure that:
ATOMrecords (rather than
Below you can find an example as to how a phospho-serine should look like:
ATOM 5776 N SER B 10 -19.024 43.939 120.740 1.00 0.00 ATOM 5777 CA SER B 10 -20.442 43.615 120.653 1.00 0.00 ATOM 5778 C SER B 10 -20.869 42.699 121.792 1.00 0.00 ATOM 5779 O SER B 10 -20.125 41.804 122.194 1.00 0.00 ATOM 5780 CB SER B 10 -20.750 42.972 119.314 1.00 0.00 ATOM 5781 OG SER B 10 -22.089 42.569 119.219 1.00 0.00 ATOM 5782 P SER B 10 -22.461 41.858 117.817 1.00 0.00 ATOM 5783 O1P SER B 10 -24.008 41.465 117.873 1.00 0.00 ATOM 5784 O2P SER B 10 -21.536 40.564 117.675 1.00 0.00 ATOM 5785 O3P SER B 10 -22.170 42.912 116.653 1.00 0.00
Note: this section was added for convenience, but may be out-dated. It's best to also look at the full options list, to make sure you're looking at the most updated listing of options.
||list of numbers||Length(s) of derived peptides||10|
||true/false||Makes derivation go faster by skipping peptides with 0 interface score||true|
||true/false||Output pose with peptide cut out (best one for each chain pair)||false|
||true/false||Output each cyclic peptide pose (those that are modeled; which is determined by -optimize_cyclic_threshold)||false|
||true/false||Output each receptor-partner pose as PeptiDerive sees it, i.e. after preparation (minimization and disulfide detection)||false|
||true/false||Send PeptideDeriver output to a file (.peptiderive.txt)||true|
||list of characters||Only use chains listed here as receptors. When empty, consider all chains.||empty|
||list of characters||Only use chains listed here as partners. When empty, consider all chains. For each receptor-partner pair, a peptide is derived from the partner.||empty|
||true/false||Perform minimization before everything.||true|
||real number||Value of peptide interface score percent of total isc from which to optimize cyclic peptide||0.35|
||string||The format of the report. Either
Depending on the value of the
report_format option, PeptiDerive outputs one of two formats
Markdown output is readable and self-explanatory. This is what we recommend for single-structure (or several-structure) runs.
Note that numbering of residues is sequential, as opposed to author numbering. For the Disulfide info column contents format, see the Basic format description for
basic report format is stripped down of almost all descriptive elements, but it's easily parsable and is currently what we use for bulk runs.
The output is in the following format:
> chain_pair: receptor= [receptor_chain_id] partner= [partner_chain_id] total_isc= [total_interface_score] >> peptide_length: [sliding_window_length] [entry_type] [seq_res_num] [peptide_interface_score] [disulfide_info]
total_interface_scoreis the ΔΔGAB of the complex (see Algorithm, above).
0for a sliding window entry (one per residue, except for the last N ones, where N is the sliding window size, and of peptides with no contribution to binding)
1to signify the best (linear) scoring peptide for the current chain pair and sliding window length
2to signify the best cyclic scoring peptide (ditto)
seq_res_num is the sequential residue number in a chain of the first peptide position (as opposed to author numbering)
peptide_interface_scoreis the ΔΔGApepB
disulfide_infois a string describing the residues for a putative cyclic peptide, if one was determined to be relevant, and - if it was modeled (depending on whether the relative linear score is above the
optimize_cyclic_threshold) - the interface score of the cyclic peptide.
In the future, we're hoping to create a
FeatureReporter to allow aggregation of output to a database.