ArticleJournal of chemical information and modeling2022
Alchemical Free Energy Calculations to Investigate Protein-Protein Interactions: the Case of the CDC42/PAK1 Complex.
Article in Journal of chemical information and modeling, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Toward Relative Redox Potential Predictions in Flavoproteins: Treatment of a Charge-Changing Mutation in Alchemical Free Energy Simulations.Journal of chemical theory and computation · 2026Article
- Molecular Modeling of the Pathogenetic Mechanisms of Neuropsychiatric Disorders.International journal of molecular sciences · 2026Review
- Evolutionary Constraints Guide AlphaFold2 in Predicting Alternative Conformations and Inform Rational Mutation Design.Journal of chemical information and modeling · 2025Article
- Multiple Topology Replica Exchange of Expanded Ensembles for Multidimensional Alchemical Calculations.Journal of chemical theory and computation · 2025Article
- Protocols for Metallo- and Serine-β-Lactamase Free Energy Predictions: Insights from Cross-Class Inhibitors.The journal of physical chemistry. B · 2024Article
- Identifying and Overcoming the Sampling Challenges in Relative Binding Free Energy Calculations of a Model Protein:Protein Complex.Journal of chemical theory and computation · 2023Article
- Identifying and overcoming the sampling challenges in relative binding free energy calculations of a model protein:protein complex.bioRxiv : the preprint server for biology · 2023Article
- Role of Dynamics and Mutations in Interactions of a Zinc Finger Antiviral Protein with CG-rich Viral RNA.Journal of chemical information and modeling · 2023Article
- Exploring PROTAC Cooperativity with Coarse-Grained Alchemical Methods.The journal of physical chemistry. B · 2023Article
- Alchemical Free-Energy Calculations of Watson-Crick and Hoogsteen Base Pairing Interconversion in DNA.Journal of chemical theory and computation · 2022Article
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Authors and funding
5 authors.
Funding
Abstract
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.
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