Alchemical Free Energy Calculations to Investigate Protein–Protein Interactions: the Case of the CDC42/PAK1 Complex
| Autor: | Maria Antonietta La Serra, Pietro Vidossich, Isabella Acquistapace, Anand K. Ganesan, Marco De Vivo |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Medicinal & Biomolecular Chemistry
General Chemical Engineering Proteins Computation Theory and Mathematics General Chemistry Protein Serine-Threonine Kinases Library and Information Sciences Computer Science Applications Medicinal and Biomolecular Chemistry p21-Activated Kinases Theoretical and Computational Chemistry Mutagenesis Mutation Genetics Generic health relevance Cancer |
| Zdroj: | Journal of chemical information and modeling, vol 62, iss 12 |
| ISSN: | 1549-960X 1549-9596 |
| DOI: | 10.1021/acs.jcim.2c00348 |
| Popis: | Here, we show that alchemical free energy calculations can quantitatively compute the effect of mutations at the protein-protein interface. As a test case, we have used the protein complex formed by the small Rho-GTPase CDC42 and its downstream effector PAK1, a serine/threonine kinase. Notably, the CDC42/PAK1 complex offers a wealth of structural, mutagenesis, and binding affinity data because of its central role in cellular signaling and cancer progression. In this context, we have considered 16 mutations in the CDC42/PAK1 complex and obtained excellent agreement between computed and experimental data on binding affinity. Importantly, we also show that a careful analysis of the side-chain conformations in the mutated amino acids can considerably improve the computed estimates, solving issues related to sampling limitations. Overall, this study demonstrates that alchemical free energy calculations can conveniently be integrated into the design of experimental mutagenesis studies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|