Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces
Rational design of specific inhibitors of protein-protein interactions is desirable for drug design to control cellular signal transduction but also for studying protein-protein interaction networks. We have developed a rapid computational approach to rationally design cyclic peptides that potential...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Chemistry |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fchem.2020.573259/full |
| _version_ | 1818207966404280320 |
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| author | Brianda L. Santini Martin Zacharias |
| author_facet | Brianda L. Santini Martin Zacharias |
| author_sort | Brianda L. Santini |
| collection | DOAJ |
| description | Rational design of specific inhibitors of protein-protein interactions is desirable for drug design to control cellular signal transduction but also for studying protein-protein interaction networks. We have developed a rapid computational approach to rationally design cyclic peptides that potentially bind at desired regions of the interface of protein-protein complexes. The methodology is based on comparing the protein backbone structure of short peptide segments (epitopes) at the protein-protein interface with a collection of cyclic peptide backbone structures. A cyclic peptide that matches the backbone structure of the segment is used as a template for a binder by adapting the amino acid side chains to the side chains found in the target complex. For a small library of cyclic peptides with known high resolution structures we found for the majority (~82%) of 154 protein-protein complexes at least one very well fitting match for a cyclic peptide template to a protein-protein interface segment. The majority of the constructed protein-cyclic peptide complexes was very stable during Molecular Dynamics simulations and showed an interaction energy score that was typically more favorable compared to interaction scores of typical peptide-protein complexes. Our cPEPmatch approach could be a promising approach for rapid suggestion of cyclic peptide binders that could be tested experimentally and further improved by chemical modification. |
| first_indexed | 2024-12-12T04:37:19Z |
| format | Article |
| id | doaj.art-c9fb30582bd841a6b63ae3ae8aef788c |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-12-12T04:37:19Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-c9fb30582bd841a6b63ae3ae8aef788c2022-12-22T00:37:56ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462020-10-01810.3389/fchem.2020.573259573259Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein InterfacesBrianda L. SantiniMartin ZachariasRational design of specific inhibitors of protein-protein interactions is desirable for drug design to control cellular signal transduction but also for studying protein-protein interaction networks. We have developed a rapid computational approach to rationally design cyclic peptides that potentially bind at desired regions of the interface of protein-protein complexes. The methodology is based on comparing the protein backbone structure of short peptide segments (epitopes) at the protein-protein interface with a collection of cyclic peptide backbone structures. A cyclic peptide that matches the backbone structure of the segment is used as a template for a binder by adapting the amino acid side chains to the side chains found in the target complex. For a small library of cyclic peptides with known high resolution structures we found for the majority (~82%) of 154 protein-protein complexes at least one very well fitting match for a cyclic peptide template to a protein-protein interface segment. The majority of the constructed protein-cyclic peptide complexes was very stable during Molecular Dynamics simulations and showed an interaction energy score that was typically more favorable compared to interaction scores of typical peptide-protein complexes. Our cPEPmatch approach could be a promising approach for rapid suggestion of cyclic peptide binders that could be tested experimentally and further improved by chemical modification.https://www.frontiersin.org/article/10.3389/fchem.2020.573259/fullprotein-protein complexesprotein interaction inhibitionprotein binding modulationcyclo peptide designdrug design with cyclo-peptidesrational cyclo peptide binders |
| spellingShingle | Brianda L. Santini Martin Zacharias Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces Frontiers in Chemistry protein-protein complexes protein interaction inhibition protein binding modulation cyclo peptide design drug design with cyclo-peptides rational cyclo peptide binders |
| title | Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces |
| title_full | Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces |
| title_fullStr | Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces |
| title_full_unstemmed | Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces |
| title_short | Rapid in silico Design of Potential Cyclic Peptide Binders Targeting Protein-Protein Interfaces |
| title_sort | rapid in silico design of potential cyclic peptide binders targeting protein protein interfaces |
| topic | protein-protein complexes protein interaction inhibition protein binding modulation cyclo peptide design drug design with cyclo-peptides rational cyclo peptide binders |
| url | https://www.frontiersin.org/article/10.3389/fchem.2020.573259/full |
| work_keys_str_mv | AT briandalsantini rapidinsilicodesignofpotentialcyclicpeptidebinderstargetingproteinproteininterfaces AT martinzacharias rapidinsilicodesignofpotentialcyclicpeptidebinderstargetingproteinproteininterfaces |