What can we learn from molecular dynamics simulations for GPCR drug design?

Tautermann, Christofer S.; Seeliger, Daniel; Kriegl, Jan M.

doi:10.1016/j.csbj.2014.12.002

Cited by 60 publications

(53 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MD simulations provide atomistic detail of biomolecular processes at high spatial and time resolution and proved extremely useful in the study of GPCR dynamics, GPCR oligomer formation and in the analysis of the influence of the membrane environment on oligomerization (Sabbadin et al, 2014; Sengupta and Chattopadhyay, 2015; Tautermann et al, 2015). In general, MD simulations at atomistic resolution of biomolecular systems are limited to the timescale of hundreds of nanoseconds to a few microseconds.…”

Section: Methods To Analyze Gpcr Oligomerizationmentioning

confidence: 99%

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

2016

View full text Add to dashboard Cite

The dimerization or even oligomerization of G protein coupled receptors (GPCRs) causes ongoing, controversial debates about its functional role and the coupled biophysical, biochemical or biomedical implications. A continously growing number of studies hints to a relation between oligomerization and function of GPCRs and strengthens the assumption that receptor assembly plays a key role in the regulation of protein function. Additionally, progress in the structural analysis of GPCR-G protein and GPCR-ligand interactions allows to distinguish between actively functional and non-signaling complexes. Recent findings further suggest that the surrounding membrane, i.e., its lipid composition may modulate the preferred dimerization interface and as a result the abundance of distinct dimeric conformations. In this review, the association of GPCRs and the role of the membrane in oligomerization will be discussed. An overview of the different reported oligomeric interfaces is provided and their capability for signaling discussed. The currently available data is summarized with regard to the formation of GPCR oligomers, their structures and dependency on the membrane microenvironment as well as the coupling of oligomerization to receptor function.

show abstract

Section: Methods To Analyze Gpcr Oligomerizationmentioning

confidence: 99%

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

2016

View full text Add to dashboard Cite

show abstract

“…To this end, in silico molecular dynamic modeling has served as a powerful tool to generate a series of conformations that show the physical movements of a protein. A number of existing studies through molecular dynamics (MD) investigation have successfully provided useful information for drug discovery …”

Section: Introductionmentioning

confidence: 99%

“…A number of existing studies through molecular dynamics (MD) investigation have successfully provided useful information for drug discovery. [4][5][6] In this work, we sought to obtain dynamic insights of the MlaC protein through computational modeling. To better understand dynamic motions of the MlaC protein from different organisms, we performed MD simulations of MlaC from both Ralstonia solanacearum and Acinetobacter baumannii.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamic study of MlaC protein in Gram‐negative bacteria: conformational flexibility, solvent effect and protein‐phospholipid binding

et al. 2016

View full text Add to dashboard Cite

The composition of the outer membrane in Gram-negative bacteria is asymmetric, with the lipopolysaccharides found in the outer leaflet and phospholipids in the inner leaflet. The MlaC protein transfers phospholipids from the outer to inner membrane to maintain such lipid asymmetry in the Mla pathway. In this work, we have performed molecular dynamics simulations on apo and phospholipid-bound systems to study the dynamical properties of MlaC. Our simulations show that the phospholipid forms hydrophobic interactions with the protein. Residues surrounding the entrance of the binding site exhibit correlated motions to control the site opening and closing. Lipid binding leads to increase of the binding pocket volume and precludes entry of the water molecules. However, in the absence of the phospholipid, water molecules can freely move in and out of the binding site when the pocket is open. Dehydration occurs when the pocket closes. This study provides dynamic information of the MlaC protein and may facilitate the design of antibiotics against the Mla pathway of Gram-negative bacteria.

show abstract

“…The expectation for elucidating structures of other GPCRs is not high, and a major breakthrough is needed. Thus, for the near future, structural information on many GPCRs is likely to be reached mainly by the technique of computer modelling …”

Section: Introductionmentioning

confidence: 99%

How to Choose the Suitable Template for Homology Modelling of GPCRs: 5‐HT₇ Receptor as a Test Case

Shahaf

Pappalardo

Basile³

et al. 2016

Molecular Informatics

View full text Add to dashboard Cite

G protein-coupled receptors (GPCRs) are a super-family of membrane proteins that attract great pharmaceutical interest due to their involvement in almost every physiological activity, including extracellular stimuli, neurotransmission, and hormone regulation. Currently, structural information on many GPCRs is mainly obtained by the techniques of computer modelling in general and by homology modelling in particular. Based on a quantitative analysis of eighteen antagonist-bound, resolved structures of rhodopsin family "A" receptors - also used as templates to build 153 homology models - it was concluded that a higher sequence identity between two receptors does not guarantee a lower RMSD between their structures, especially when their pair-wise sequence identity (within trans-membrane domain and/or in binding pocket) lies between 25 % and 40 %. This study suggests that we should consider all template receptors having a sequence identity ≤50 % with the query receptor. In fact, most of the GPCRs, compared to the currently available resolved structures of GPCRs, fall within this range and lack a correlation between structure and sequence. When testing suitability for structure-based drug design, it was found that choosing as a template the most similar resolved protein, based on sequence resemblance only, led to unsound results in many cases. Molecular docking analyses were carried out, and enrichment factors as well as attrition rates were utilized as criteria for assessing suitability for structure-based drug design.

show abstract

What can we learn from molecular dynamics simulations for GPCR drug design?

Cited by 60 publications

References 82 publications

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

Molecular dynamic study of MlaC protein in Gram‐negative bacteria: conformational flexibility, solvent effect and protein‐phospholipid binding

How to Choose the Suitable Template for Homology Modelling of GPCRs: 5‐HT₇ Receptor as a Test Case

Contact Info

Product

Resources

About

What can we learn from molecular dynamics simulations for GPCR drug design?

Cited by 60 publications

References 82 publications

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

Membrane-Mediated Oligomerization of G Protein Coupled Receptors and Its Implications for GPCR Function

Molecular dynamic study of MlaC protein in Gram‐negative bacteria: conformational flexibility, solvent effect and protein‐phospholipid binding

How to Choose the Suitable Template for Homology Modelling of GPCRs: 5‐HT7 Receptor as a Test Case

Contact Info

Product

Resources

About

How to Choose the Suitable Template for Homology Modelling of GPCRs: 5‐HT₇ Receptor as a Test Case