The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Molecular Dynamics—Solvated Interaction Energy Studies of Protein–Protein Interactions: The MP1–p14 Scaffolding Complex
Abstract
Using the MP1-p14 scaffolding complex from the mitogen-activated protein kinase signaling pathway as model system, we explored a structure-based computational protocol to probe and characterize binding affinity hot spots at protein-protein interfaces. Hot spots are located by virtual alanine-scanning consensus predictions over three different energy functions and two different single-structure representations of the complex. Refined binding affinity predictions for select hot-spot mutations are carried out by applying first-principle methods such as the molecular mechanics generalized Born surface area (MM-GBSA) and solvated interaction energy (SIE) to the molecular dynamics (MD) trajectories for mutated and wild-type complexes. Here, predicted hot-spot residues were actually mutated to alanine, and crystal structures of the mutated complexes were determined. Two mutated MP1-p14 complexes were investigated, the p14(Y56A)-mutated complex and the MP1(L63A,L65A)-mutated complex. Alternative ways to generate MD ensembles for mutant complexes, not relying on crystal structures for mutated complexes, were also investigated. The SIE function, fitted on protein-ligand binding affinities, gave absolute binding affinity predictions in excellent agreement with experiment and outperformed standard MM-GBSA predictions when tested on the MD ensembles of Ras-Raf and Ras-RalGDS protein-protein complexes. For wild-type and mutant MP1-p14 complexes, SIE predictions of relative binding affinities were supported by a yeast two-hybrid assay that provided semiquantitative relative interaction strengths. Results on the MP1-mutated complex suggested that SIE predictions deteriorate if mutant MD ensembles are approximated by just mutating the wild-type MD trajectory. The SIE data on the p14-mutated complex indicated feasibility for generating mutant MD ensembles from mutated wild-type crystal structure, despite local structural differences observed upon mutation. For energetic considerations, this would circumvent costly needs to produce and crystallize mutated complexes. The sensitized protein-protein interface afforded by the p14(Y56A) mutation identified here has practical applications in screening-based discovery of first-generation small-molecule hits for further development into specific modulators of the mitogen-activated protein kinase signaling pathway.
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“The structures of LAMTOR2, LAMTOR3 and LAMTOR5 were the first to be characterized prior to the discovery of the Ragulator complex (Kurzbauer et al., 2004; Cui et al., 2008; Lunin et al., 2004; Qian et al., 2005; Garcia-Saez et al., 2011), revealing roadblock folds for the individual LAMTOR3 and LAMTOR5 monomers, and the formation of MP1/p14 heterodimers by edge-to-edge juxtaposition of the roadb”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Cui et al., 2008
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Metadata
- Authors
- Cui, Q., Sulea, T., Schrag, J. D., Munger, C., Hung, M.-N., Naïm, M., Cygler, M., & Purisima, E. O.
- Affiliations
- Biotechnology Research Institute (CA)
- McGill University (CA)
- Corresponding author
- Purisima, Enrico O.
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2008-06
- Volume
- 379
- Issue
- 4
- Pages
- 787-802
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W2071919488
- Cited by
- 162
- References
- 56
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 13 · 2023: 9 · 2022: 10 · 2021: 4 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 8 · 2016: 5 · 2015: 10 · 2014: 16 · 2013: 14 · 2012: 9
- FWCI
- 5.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- NPARC (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Physics and Astronomy › Atomic and Molecular Physics, and Optics › Advanced Chemical Physics Studies
- Keywords
- protein-protein interaction, MAPK signaling, alanine scanning, MM-GBSA, yeast two-hybrid, small molecule hits
- MeSH terms
- Binding Sites, Models, Molecular, Proteins, Recombinant Proteins, Thermodynamics, Mutagenesis, Site-Directed, Crystallography, X-Ray, Amino Acid Substitution, Two-Hybrid System Techniques, MAP Kinase Signaling System, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Protein Interaction Domains and Motifs
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