Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics

Ferraro, Mariarosaria; Masetti, Matteo; Recanatini, Maurizio; Cavalli, Andrea; Bottegoni, Giovanni

doi:10.1371/journal.pone.0166196

Cited by 24 publications

(37 citation statements)

References 71 publications

(109 reference statements)

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“…The simulation, moreover, reveals the dynamic component of cholesterol interactions at this site, as multiple binding modes are detected ( Figure S3A ), in line with what has been already described for the corresponding cholesterol site in the serotonin transporter. 45 …”

Section: Resultsmentioning

confidence: 99%

Lipid–Protein Interactions Are Unique Fingerprints for Membrane Proteins

et al. 2018

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Cell membranes contain hundreds of different proteins and lipids in an asymmetric arrangement. Our current understanding of the detailed organization of cell membranes remains rather elusive, because of the challenge to study fluctuating nanoscale assemblies of lipids and proteins with the required spatiotemporal resolution. Here, we use molecular dynamics simulations to characterize the lipid environment of 10 different membrane proteins. To provide a realistic lipid environment, the proteins are embedded in a model plasma membrane, where more than 60 lipid species are represented, asymmetrically distributed between the leaflets. The simulations detail how each protein modulates its local lipid environment in a unique way, through enrichment or depletion of specific lipid components, resulting in thickness and curvature gradients. Our results provide a molecular glimpse of the complexity of lipid–protein interactions, with potentially far-reaching implications for our understanding of the overall organization of real cell membranes.

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Section: Resultsmentioning

confidence: 99%

Lipid–Protein Interactions Are Unique Fingerprints for Membrane Proteins

et al. 2018

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“…Furthermore, the CHOL site observed on the EC part of TM12 in the hSERT crystal structures is not found in the CG-hSERT simulation. A study performed by Ferraro et al using a similar CG MD approach and an early homology model for hSERT (a low resolution model based on LeuT) [ 44 ], similarly identified site 1 and 2 [ 45 ].…”

Section: Resultsmentioning

confidence: 99%

A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition

et al. 2018

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Monoamine transporters (MATs) carry out neurotransmitter reuptake from the synaptic cleft, a key step in neurotransmission, which is targeted in the treatment of neurological disorders. Cholesterol (CHOL), a major component of the synaptic plasma membrane, has been shown to exhibit a modulatory effect on MATs. Recent crystal structures of the dopamine transporter (DAT) revealed the presence of two conserved CHOL-like molecules, suggesting a functional protein-CHOL direct interaction. Here, we present extensive atomistic molecular dynamics (MD) simulations of DAT in an outward-facing conformation. In the absence of bound CHOL, DAT undergoes structural changes reflecting early events of dopamine transport: transition to an inward-facing conformation. In contrast, in the presence of bound CHOL, these conformational changes are inhibited, seemingly by an immobilization of the intracellular interface of transmembrane helix 1a and 5 by CHOL. We also provide evidence, from coarse grain MD simulations that the CHOL sites observed in the DAT crystal structures are preserved in all human monoamine transporters (dopamine, serotonin and norepinephrine), suggesting that our findings might extend to the entire family.

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“…Finally, coarse-grained variants can also be designed. One such application comes from Ferraro et al, who mapped cholesterol binding sites on the surface of a homology-derived model of the serotonin transporter [ 64 ].…”

Section: Plugging MD Into Static Modeling Frameworkmentioning

confidence: 99%

Dynamic Docking: A Paradigm Shift in Computational Drug Discovery

et al. 2017

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Molecular docking is the methodology of choice for studying in silico protein-ligand binding and for prioritizing compounds to discover new lead candidates. Traditional docking simulations suffer from major limitations, mostly related to the static or semi-flexible treatment of ligands and targets. They also neglect solvation and entropic effects, which strongly limits their predictive power. During the last decade, methods based on full atomistic molecular dynamics (MD) have emerged as a valid alternative for simulating macromolecular complexes. In principle, compared to traditional docking, MD allows the full exploration of drug-target recognition and binding from both the mechanistic and energetic points of view (dynamic docking). Binding and unbinding kinetic constants can also be determined. While dynamic docking is still too computationally expensive to be routinely used in fast-paced drug discovery programs, the advent of faster computing architectures and advanced simulation methodologies are changing this scenario. It is feasible that dynamic docking will replace static docking approaches in the near future, leading to a major paradigm shift in in silico drug discovery. Against this background, we review the key achievements that have paved the way for this progress.

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Mapping Cholesterol Interaction Sites on Serotonin Transporter through Coarse-Grained Molecular Dynamics

Cited by 24 publications

References 71 publications

Lipid–Protein Interactions Are Unique Fingerprints for Membrane Proteins

Lipid–Protein Interactions Are Unique Fingerprints for Membrane Proteins

A direct interaction of cholesterol with the dopamine transporter prevents its out-to-inward transition

Dynamic Docking: A Paradigm Shift in Computational Drug Discovery

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