Binding Ensembles of p53-MDM2 Peptide Inhibitors by Combining Bayesian Inference and Atomistic Simulations
| Autor: | Alberto Perez, Lijun Lang |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Protein Conformation Pharmaceutical Science Peptide p53 6 Computational biology Molecular Dynamics Simulation Bayesian inference 01 natural sciences Article P53 mdm2 Analytical Chemistry lcsh:QD241-441 03 medical and health sciences advanced sampling 5 lcsh:Organic chemistry 0103 physical sciences Drug Discovery Cluster Analysis Protein Interaction Domains and Motifs Physical and Theoretical Chemistry 030304 developmental biology MELD×MD 4 chemistry.chemical_classification binding 2 0303 health sciences Virtual screening MDM2 7 010304 chemical physics Organic Chemistry Rational design Bayes Theorem Proto-Oncogene Proteins c-mdm2 Statistical mechanics molecular dynamics 3 Small molecule IDP 1 Intrinsically Disordered Proteins Folding (chemistry) chemistry Chemistry (miscellaneous) Molecular Medicine Tumor Suppressor Protein p53 Peptides |
| Zdroj: | Molecules, Vol 26, Iss 198, p 198 (2021) Molecules Volume 26 Issue 1 |
| ISSN: | 1420-3049 |
| Popis: | Designing peptide inhibitors of the p53-MDM2 interaction against cancer is of wide interest. Computational modeling and virtual screening are a well established step in the rational design of small molecules. But they face challenges for binding flexible peptide molecules that fold upon binding. We look at the ability of five different peptides, three of which are intrinsically disordered, to bind to MDM2 with a new Bayesian inference approach (MELD× MD). The method is able to capture the folding upon binding mechanism and differentiate binding preferences between the five peptides. Processing the ensembles with statistical mechanics tools depicts the most likely bound conformations and hints at differences in the binding mechanism. Finally, the study shows the importance of capturing two driving forces to binding in this system: the ability of peptides to adopt bound conformations (&Delta Gconformation) and the interaction between interface residues (&Delta Ginteraction). |
| Databáze: | OpenAIRE |
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