Authors: Nir London, Barak Raveh, Dana Movshovitz-Attias, Yuval Sadan, Orly Marcu, Ora Schueler-Furman
The documentation was last updated on Feb 23, 2015, by Yuval Sadan. 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).
We have used this protocol in the past to evaluate the fraction of interfaces that could be inhibited by a peptide or a peptidomimetic. We found on two representative benchmarks that this amounts to around 50% of the 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 of course, 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, for a set of solved structures of structures of small molecules that inhibit protein interactions in complex with their partner 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.
Note: documentation for filtering and modeling cyclic peptides is pending.
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 in 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)
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 numbers for this chain (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. Better documentation for this is pending.
In the future, we're hoping to create a
FeatureReporter to allow aggregation of output to a database.