ArticlePLoS computational biology2012
Finding a needle in a haystack: the role of electrostatics in target lipid recognition by PH domains.
Article in PLoS computational biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- On the possibility of the existence of orienting hydrodynamic steering effects in the kinetics of receptor-ligand association.European biophysics journal : EBJ · 2023Review
- Article
- Article
- Membrane surface recognition by the ASAP1 PH domain and consequences for interactions with the small GTPase Arf1.Science advances · 2020Article
- Capturing Choline-Aromatics Cation-π Interactions in the MARTINI Force Field.Journal of chemical theory and computation · 2020Article
- Microscopic Characterization of GRP1 PH Domain Interaction with Anionic Membranes.Journal of computational chemistry · 2020Article
- Multiple lipid binding sites determine the affinity of PH domains for phosphoinositide-containing membranes.Science advances · 2020Article
- Characterization of Lipid-Protein Interactions and Lipid-Mediated Modulation of Membrane Protein Function through Molecular Simulation.Chemical reviews · 2019Review
- Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance.Chemical reviews · 2019Article
- Computational Modeling of Realistic Cell Membranes.Chemical reviews · 2019Review
- Polyphosphoinositide-Binding Domains: Insights from Peripheral Membrane and Lipid-Transfer Proteins.Advances in experimental medicine and biology · 2019Review
- Multiple interactions between an Arf/GEF complex and charged lipids determine activation kinetics on the membrane.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Association of Peripheral Membrane Proteins with Membranes: Free Energy of Binding of GRP1 PH Domain with Phosphatidylinositol Phosphate-Containing Model Bilayers.The journal of physical chemistry letters · 2016Article
- A Role for Weak Electrostatic Interactions in Peripheral Membrane Protein Binding.Biophysical journal · 2016Article
- Structures of the EphA2 Receptor at the Membrane: Role of Lipid Interactions.Structure (London, England : 1993) · 2016Article
- SDA 7: A modular and parallel implementation of the simulation of diffusional association software.Journal of computational chemistry · 2015Article
- Inositol pyrophosphates: why so many phosphates?Advances in biological regulation · 2015Review
- Computational Analysis of the Binding Specificities of PH Domains.BioMed research international · 2015Article
- CHARMM-GUI Membrane Builder toward realistic biological membrane simulations.Journal of computational chemistry · 2014Article
- Solvent-Free, Highly Coarse-Grained Models for Charged Lipid Systems.Journal of chemical theory and computation · 2014Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Interactions between protein domains and lipid molecules play key roles in controlling cell membrane signalling and trafficking. The pleckstrin homology (PH) domain is one of the most widespread, binding specifically to phosphatidylinositol phosphates (PIPs) in cell membranes. PH domains must locate specific PIPs in the presence of a background of approximately 20% anionic lipids within the cytoplasmic leaflet of the plasma membrane. We investigate the mechanism of such recognition via a multiscale procedure combining Brownian dynamics (BD) and molecular dynamics (MD) simulations of the GRP1 PH domain interacting with phosphatidylinositol (3,4,5)-trisphosphate (PI(3,4,5)P₃). The interaction of GRP1-PH with PI(3,4,5)P₃ in a zwitterionic bilayer is compared with the interaction in bilayers containing different levels of anionic 'decoy' lipids. BD simulations reveal both translational and orientational electrostatic steering of the PH domain towards the PI(3,4,5)P₃-containing anionic bilayer surface. There is a payoff between non-PIP anionic lipids attracting the PH domain to the bilayer surface in a favourable orientation and their role as 'decoys', disrupting the interaction of GRP1-PH with the PI(3,4,5)P₃ molecule. Significantly, approximately 20% anionic lipid in the cytoplasmic leaflet of the bilayer is nearly optimal to both enhance orientational steering and to localise GRP1-PH proximal to the surface of the membrane without sacrificing its ability to locate PI(3,4,5)P₃ within the bilayer plane. Subsequent MD simulations reveal binding to PI(3,4,5)P₃, forming protein-phosphate contacts comparable to those in X-ray structures. These studies demonstrate a computational framework which addresses lipid recognition within a cell membrane environment, offering a link between structural and cell biological characterisation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.