Improved Replica Exchange Method for Native-State Protein Sampling

Moors, Samuel L. C.; Michielssens, Servaas; Ceulemans, Arnout

doi:10.1021/ct100493v

Cited by 50 publications

(49 citation statements)

References 33 publications

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“…Hence, the receptor is kept at the temperature of interest, T 0 , while the ligand is heated, allowing it to cross potential energy barriers more rapidly. The scaling factor for E RL is intermediate between those for E R and E L and has been shown to prevent the loss of protein secondary structure at high temperatures, 11−13 which was sometimes observed with earlier choices of scaling factor. 9 …”

Section: Methodsmentioning

confidence: 98%

Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering

Cole

Tirado‐Rives

Jorgensen

2014

J. Chem. Theory Comput.

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With a view to improving the consistency of free energy perturbation calculations in Monte Carlo simulations of protein–ligand complexes, we have implemented the replica exchange with solute tempering (REST) method in the MCPRO software. By augmenting the standard REST approach with regular attempted jumps in selected dihedral angles, our combined method facilitates sampling of ligand binding modes that are separated by high free energy barriers and ensures that computed free energy changes are considerably less dependent on the starting conditions and the chosen mutation pathway than those calculated with standard Monte Carlo sampling. We have applied the enhanced sampling method to the calculation of the activities of seven non-nucleoside inhibitors of HIV-1 reverse transcriptase, and its Tyr181Cys variant, and have shown that a range of binding orientations is possible depending on the nature of the ligand and the presence of mutations at the binding site.

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Section: Methodsmentioning

confidence: 98%

Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering

Cole

Tirado‐Rives

Jorgensen

2014

J. Chem. Theory Comput.

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“…Another method based on the idea of solute tempering has also been proposed by Moors et al [192]. They introduced the replica exchange with flexible tempering method, in which a part of the solute molecule, e.g., flexible hinges or loops of the protein, is heated up in order to enhance domain motions of proteins.…”

Section: Enhanced Conformational Sampling Methodsmentioning

confidence: 99%

Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms

Mori

Miyashita²,

et al. 2016

Biochimica et Biophysica Acta (BBA) - Biomembranes

116

108

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This paper reviews various enhanced conformational sampling methods and explicit/implicit solvent/membrane models, as well as their recent applications to the exploration of the structure and dynamics of membranes and membrane proteins. Molecular dynamics simulations have become an essential tool to investigate biological problems, and their success relies on proper molecular models together with efficient conformational sampling methods. The implicit representation of solvent/membrane environments is reasonable approximation to the explicit all-atom models, considering the balance between computational cost and simulation accuracy. Implicit models can be easily combined with replica-exchange molecular dynamics methods to explore a wider conformational space of a protein. Other molecular models and enhanced conformational sampling methods are also briefly discussed. As application examples, we introduce recent simulation studies of glycophorin A, phospholamban, amyloid precursor protein, and mixed lipid bilayers and discuss the accuracy and efficiency of each simulation model and method. This article is part of a Special Issue entitled: Membrane Proteins. Guest Editors: J.C. Gumbart and Sergei Noskov.

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“…[27] Initial peptide structures were modeled to have approximately circular shape. [23] As et of 16 replicas was used with scaling factors ranging from 1t o0 .2, corresponding to "effective" solute temperatures ranging from 300 to 1500 K. Exchange attempts between replicas were performed every 2ps. After relaxation, the system was equilibrated for 100 ps at constant pressure with at ime step of 2f sa nd keeping all bonds fixed.…”

Section: Molecular Dynamicsmentioning

confidence: 99%

Rational Design of Nanobody80 Loop Peptidomimetics: Towards Biased β₂ Adrenergic Receptor Ligands

Martin

Moors

Danielsen

et al. 2017

Chemistry A European J

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G protein-coupled receptors (GPCRs) play an important role in many cellular responses; as such, their mechanism of action is of utmost interest. To gain insight into the active conformation of GPCRs, the X-ray crystal structures of nanobody (Nb)-stabilized β -adrenergic receptor (β AR) have been reported. Nb80, in particular, is able to bind the intracellular G protein binding site of β AR and stabilize the receptor in an active conformation. Within Nb80, the complementarity-determining region 3 (CDR3) is responsible for most of the binding interactions. Hence, we hypothesized that peptidomimetics of the CDR3 loop might be sufficient for binding to the receptor, inhibiting the interaction of β AR with intracellular GPCR interacting proteins (e.g., G proteins). Based on previous crystallographic data, a set of peptidomimetics were synthesized that, similar to the Nb80 CDR3 loop, adopt a β-hairpin conformation. Syntheses, conformational analysis, binding and functional in vitro assays, as well as internalization experiments, were performed. We demonstrate that peptidomimetics can structurally mimic the CDR3 loop of a nanobody and its function by inhibiting G protein coupling as measured by partial inhibition of cAMP production.

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Improved Replica Exchange Method for Native-State Protein Sampling

Cited by 50 publications

References 33 publications

Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering

Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering

Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms

Rational Design of Nanobody80 Loop Peptidomimetics: Towards Biased β₂ Adrenergic Receptor Ligands

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Improved Replica Exchange Method for Native-State Protein Sampling

Cited by 50 publications

References 33 publications

Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering

Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering

Molecular dynamics simulations of biological membranes and membrane proteins using enhanced conformational sampling algorithms

Rational Design of Nanobody80 Loop Peptidomimetics: Towards Biased β2 Adrenergic Receptor Ligands

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Rational Design of Nanobody80 Loop Peptidomimetics: Towards Biased β₂ Adrenergic Receptor Ligands