Protein–protein recognition and interaction hot spots in an antigen–antibody complex: Free energy decomposition identifies “efficient amino acids”

Lafont, Virginie; Schaefer, Michael; Stote, Roland H.; Altschuh, Danièle; Dejaegere, Annick

doi:10.1002/prot.21259

Cited by 95 publications

(120 citation statements)

References 75 publications

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“…2 (31); for water, the CHARMM modified TIP3 model (32) was used. Electrostatic interactions were decomposed into individual amino acid contributions as previously described (27,(33)(34)(35), and intermolecular interactions and desolvation contributions were separated. van der Waals' interactions between the ligand and LBD were computed with the CHARMM force field using a Lennard-Jones 6 -12 potential, (with a switching function between 8.5 and 12.5 Å for cutoff) and decomposed into individual amino acid contributions.…”

Section: Methodsmentioning

confidence: 99%

Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor

Browning

Martin

Loch

et al. 2007

Journal of Biological Chemistry

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The insect steroid hormone 20-hydroxyecdysone (20E) binds to its cognate nuclear receptor composed of the ecdysone receptor (EcR) and Ultraspiracle (USP) and triggers the main developmental transitions, in particular molting and metamorphosis. We present the crystal structure of the ligand-binding domains of EcR/USP in complex with 20E at 2.4 Å resolution and compare it with published structures of EcR/USP bound to ponasterone A (ponA). ponA is essentially identical to 20E but lacks the 25-OH group of 20E. The structure of 20E-bound EcR indicates that an additional hydrogen bond is formed compared with the ponA-bound receptor, yet, paradoxically, ponA has a significantly higher affinity for EcR than 20E.

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Section: Methodsmentioning

confidence: 99%

Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor

Browning

Martin

Loch

et al. 2007

Journal of Biological Chemistry

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“…Notably, although it is possible to analyze individual contributions to conformational entropies (Fischer et al 2001), the simplification saves the significant and unnecessary computational cost. Moreover, it has been applied successfully in the context of identifying interaction energy ''hot spots'' in antigen-antibody complexes (Lafont et al 2007). Therefore, in this section, we calculated only a subset of terms entering the MM-GBSA, i.e., the electrostatic, the van der Waals, and the hydrophobic contributions.…”

Section: Free Energy Decompositionmentioning

confidence: 99%

Dynamic mechanisms for pre-miRNA binding and export by Exportin-5

Wang¹,

Xue²,

Zhi³

et al. 2011

RNA

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The biogenesis and function of mature microRNAs (miRNAs) is dependent on the nuclear export of miRNA precursors (premiRNA) by . To characterize the molecular mechanisms of how pre-miRNA is recognized and transported by Exp5, we have performed 21 molecular dynamic (MD) simulations of RNA-bound Exp5 (Exp5-RanGTP-premiRNA, Exp5-RanGDP-premiRNA, Exp5-premiRNA), RNA-unbound Exp5 (Exp5-RanGTP, Exp5-RanGDP, apo-Exp5), and pre-miRNA. Our simulations with standard MD, steered molecular dynamics (SMD), and energy analysis have shown that (1) Free Exp5 undergoes extensive opening motion, and in this way facilitates the RanGTP binding. (2) RanGTP efficiently regulates the association/dissociation of pre-miRNA to its complex by inducing conformational changes in the HEAT-repeat helix stacking of Exp5. (3) The GTP hydrolysis prevents Ran from rebinding to Exp5 by regulating the hydrophobic interfaces and salt bridges between Ran and Exp5. (4) The transition from the A9-form to the A-form of the pre-miRNA modulates the structural complementarities between the protein and the pre-miRNA, thus promoting efficient assembly of the complex. (5) The baseflipping process (from the closed to the fully flipped state) of the 2-nt 39 overhang is a prerequisite for the pre-miRNA recognition by Exp5, which occurs in a sequence-independent manner as evidenced by the fact that different 2-nt 39 overhangs bind to Exp5 in essentially the same way. And finally, a plausible mechanism of the pre-miRNA export cycle has been proposed explaining how the protein-protein and protein-RNA interactions are coordinated in physiological conditions.

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“…In this study, we use a protocol based on the MM/PBSA method (22,24,26,32) where conformations extracted from molecular dynamics simulations are processed using a simplified description for the solvent to yield an estimate of binding free energy. Individual contributions of each amino acid to the complex formation are estimated, and important energetic amino acid "hot spots" are identified.…”

Section: Methodsmentioning

confidence: 99%

“…Here we applied the MM/PBSA method to investigate the factors that give rise to promiscuous binding by the Bcl-xl anti-apoptotic protein. We used a protocol presented earlier (24) to decompose the free energy of binding into individual amino acid contributions to map out the interactions that have a dominant role in the formation of these complexes, i.e. between anti-apoptotic proteins (Bcl-xl and Bcl-w) and BH3 peptides derived from the pro-apoptotic proteins Bid (27), Bad (28), Bim (30), and Bak (31).…”

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confidence: 99%

Molecular Basis for Bcl-2 Homology 3 Domain Recognition in the Bcl-2 Protein Family

Moroy

Martin

Dejaegere

et al. 2009

Journal of Biological Chemistry

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The proteins of the Bcl-2 family are important regulators of apoptosis, or programmed cell death. These proteins regulate this fundamental biological process via the formation of heterodimers involving both pro-and anti-apoptotic family members. Disruption of the balance between anti-and pro-apoptotic Bcl-2 proteins is the cause of numerous pathologies. Bcl-xl, an anti-apoptotic protein of this family, is known to form heterodimers with multiple pro-apoptotic proteins, such as Bad, Bim, Bak, and Bid. To elucidate the molecular basis of this recognition process, we used molecular dynamics simulations coupled with the Molecular Mechanics/Poisson-Boltzmann Surface Area approach to identify the amino acids that make significant energetic contributions to the binding free energy of four complexes formed between Bcl-xl and pro-apoptotic Bcl-2 homology 3 peptides. A fifth protein-peptide complex composed of another anti-apoptotic protein, Bcl-w, in complex with the peptide from Bim was also studied. The results identified amino acids of both the anti-apoptotic proteins as well as the Bcl-2 homology 3 (BH3) domains of the pro-apoptotic proteins that make strong, recurrent interactions in the protein complexes. The calculations show that the two anti-apoptotic proteins, Bcl-xl and Bcl-w, share a similar recognition mechanism. Our results provide insight into the molecular basis for the promiscuous nature of this molecular recognition process by members of the Bcl-2 protein family. These amino acids could be targeted in the design of new mimetics that serve as scaffolds for new antitumoral molecules.

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Protein–protein recognition and interaction hot spots in an antigen–antibody complex: Free energy decomposition identifies “efficient amino acids”

Cited by 95 publications

References 75 publications

Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor

Critical Role of Desolvation in the Binding of 20-Hydroxyecdysone to the Ecdysone Receptor

Dynamic mechanisms for pre-miRNA binding and export by Exportin-5

Molecular Basis for Bcl-2 Homology 3 Domain Recognition in the Bcl-2 Protein Family

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