scholarly journals The SPICA Coarse-Grained Force Field for Proteins and Peptides

2021 ◽  
Author(s):  
Shuhei Kawamoto ◽  
Huihui Liu ◽  
Sangjae Seo ◽  
Yusuke Miyazaki ◽  
Mayank Dixit ◽  
...  
Keyword(s):  
Force Field ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Coarse Grained ◽  
Transmembrane Helices ◽  
Free Energies ◽  
Transmembrane Peptides ◽  
Energy Profiles ◽  
Protein Model ◽  
Preliminary Version

ABSTRACTA coarse-grained (CG) model for peptides and proteins was developed as an extension of the SPICA (Surface Property fItting Coarse grAined) force field (FF). The model was designed to examine membrane proteins that are fully compatible with the lipid membranes of the SPICA FF. A preliminary version of this protein model was created using thermodynamic properties, including the surface tension and density in the SPICA (formerly called SDK) FF. In this study, we improved the CG protein model to facilitate molecular dynamics (MD) simulation with a reproduction of multiple properties from both experiments and all-atom (AA) simulations. The side chain analogs reproduced the transfer free energy profiles across the lipid membrane and demonstrated reasonable dimerization free energies in water compared to those from AA-MD. A series of peptides/proteins adsorbed or penetrated into the membrane simulated by the CG-MD correctly predicted the penetration depths and tilt angles of peripheral and transmembrane peptides/proteins comparable to those in the orientation of protein in membrane (OPM) database. In addition, the dimerization free energies of several transmembrane helices within a lipid bilayer were comparable to those from experimental estimation. Application studies on a series of membrane protein assemblies, scramblases, and poliovirus capsids demonstrated a good performance of the SPICA FF.

scholarly journals Fentanyl binds to the μ-opioid receptor via the lipid membrane and transmembrane helices

2021 ◽  
Author(s):  
Katy J Sutcliffe ◽  
Robin A Corey ◽  
Steven J Charlton ◽  
Richard B Sessions ◽  
Graeme Henderson ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Lipid Membrane ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Transmembrane Helices ◽  
Opioid Agonist ◽  
The Usa ◽  
Μ Opioid Receptor ◽  
Dynamics Simulations

AbstractOverdose deaths from synthetic opioids, such as fentanyl, have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist, that is less well reversed by naloxone than morphine. Due to fentanyl’s high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by a novel binding mode to the μ-opioid receptor (MOPr).By employing coarse-grained molecular dynamics simulations and free energy calculations, we determined the routes by which fentanyl and morphine access the orthosteric pocket of MOPr.Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl takes a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices.This novel lipophilic route may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone.

scholarly journals Physical mechanisms of amyloid nucleation on fluid membranes

2020 ◽  
Vol 117 (52) ◽  
pp. 33090-33098
Author(s):  
Johannes Krausser ◽  
Tuomas P. J. Knowles ◽  
Anđela Šarić
Keyword(s):  
Lipid Membranes ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Lipid Membrane ◽  
Coarse Grained ◽  
Coarse Grained Model ◽  
Physical Mechanisms ◽  
Fluid Membranes ◽  
Protein Membrane ◽  
Protein Rich

Biological membranes can dramatically accelerate the aggregation of normally soluble protein molecules into amyloid fibrils and alter the fibril morphologies, yet the molecular mechanisms through which this accelerated nucleation takes place are not yet understood. Here, we develop a coarse-grained model to systematically explore the effect that the structural properties of the lipid membrane and the nature of protein–membrane interactions have on the nucleation rates of amyloid fibrils. We identify two physically distinct nucleation pathways—protein-rich and lipid-rich—and quantify how the membrane fluidity and protein–membrane affinity control the relative importance of those molecular pathways. We find that the membrane’s susceptibility to reshaping and being incorporated into the fibrillar aggregates is a key determinant of its ability to promote protein aggregation. We then characterize the rates and the free-energy profile associated with this heterogeneous nucleation process, in which the surface itself participates in the aggregate structure. Finally, we compare quantitatively our data to experiments on membrane-catalyzed amyloid aggregation of α-synuclein, a protein implicated in Parkinson’s disease that predominately nucleates on membranes. More generally, our results provide a framework for understanding macromolecular aggregation on lipid membranes in a broad biological and biotechnological context.

scholarly journals Curvature induction and sensing of the F-BAR protein Pacsin1 on lipid membranes via molecular dynamics simulations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Md. Iqbal Mahmood ◽  
Hiroshi Noguchi ◽  
Kei-ichi Okazaki
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Lipid Membranes ◽  
Lipid Membrane ◽  
Complex Structure ◽  
Membrane Curvature ◽  
Coarse Grained ◽  
Lateral Interaction ◽  
Bar Domain ◽  
Dynamics Simulations

Abstract F-Bin/Amphiphysin/Rvs (F-BAR) domain proteins play essential roles in biological processes that involve membrane remodelling, such as endocytosis and exocytosis. It has been shown that such proteins transform the lipid membrane into tubes. Notably, Pacsin1 from the Pacsin/Syndapin subfamily has the ability to transform the membrane into various morphologies: striated tubes, featureless wide and thin tubes, and pearling vesicles. The molecular mechanism of this interesting ability remains elusive. In this study, we performed all-atom (AA) and coarse-grained (CG) molecular dynamics simulations to investigate the curvature induction and sensing mechanisms of Pacsin1 on a membrane. From AA simulations, we show that Pacsin1 has internal structural flexibility. In CG simulations with parameters tuned from the AA simulations, spontaneous assembly of two Pacsin1 dimers through lateral interaction is observed. Based on the complex structure, we show that the regularly assembled Pacsin1 dimers bend a tensionless membrane. We also show that a single Pacsin1 dimer senses the membrane curvature, binding to a buckled membrane with a preferred curvature. These results provide molecular insights into polymorphic membrane remodelling.

scholarly journals The Automated Optimisation of a Coarse-Grained Force Field Using Free Energy Data

2020 ◽  
Author(s):  
Javier Caceres-Delpiano ◽  
Lee-Ping Wang ◽  
Jonathan W. Essex
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Degrees Of Freedom ◽  
Coarse Grained ◽  
Free Energies ◽  
Energy Data ◽  
Molecular Systems ◽  
Atomistic Models ◽  
The Cost ◽  
Long Timescales

AbstractAtomistic models provide a detailed representation of molecular systems, but are sometimes inadequate for simulations of large systems over long timescales. Coarse-grained models enable accelerated simulations by reducing the number of degrees of freedom, at the cost of reduced accuracy. New optimisation processes to parameterise these models could improve their quality and range of applicability. We present an automated approach for the optimisation of coarse-grained force fields, by reproducing free energy data derived from atomistic molecular simulations. To illustrate the approach, we implemented hydration free energy gradients as a new target for force field optimisation in ForceBalance and applied it successfully to optimise the un-charged side-chains and the protein backbone in the SIRAH protein coarse-grain force field. The optimised parameters closely reproduced hydration free energies of atomistic models and gave improved agreement with experiment.

pSPICA: A Coarse-Grained Force Field for Lipid Membranes Based on a Polar Water Model

2019 ◽  
Vol 16 (1) ◽  
pp. 782-793 ◽  
Author(s):  
Yusuke Miyazaki ◽  
Susumu Okazaki ◽  
Wataru Shinoda
Keyword(s):  
Force Field ◽  
Lipid Membranes ◽  
Coarse Grained ◽  
Water Model ◽  
Polar Water

scholarly journals Elucidating the Structural Basis of the Intracellular pH Sensing Mechanism of TASK-2 K2P Channels

2020 ◽  
Vol 21 (2) ◽  
pp. 532 ◽  
Author(s):  
Daniel Bustos ◽  
Mauricio Bedoya ◽  
David Ramírez ◽  
Guierdy Concha ◽  
Leandro Zúñiga ◽  
...  
Keyword(s):  
Ion Transport ◽  
Lipid Membrane ◽  
Structural Basis ◽  
Resting Membrane Potential ◽  
Ph Sensing ◽  
Transmembrane Helices ◽  
Energy Profiles ◽  
K2p Channels ◽  
Important Barrier ◽  
Pore Domain

Two-pore domain potassium (K2P) channels maintain the cell’s background conductance by stabilizing the resting membrane potential. They assemble as dimers possessing four transmembrane helices in each subunit. K2P channels were crystallized in “up” and “down” states. The movements of the pore-lining transmembrane TM4 helix produce the aperture or closure of side fenestrations that connect the lipid membrane with the central cavity. When the TM4 helix is in the up-state, the fenestrations are closed, while they are open in the down-state. It is thought that the fenestration states are related to the activity of K2P channels and the opening of the channels preferentially occurs from the up-state. TASK-2, a member of the TALK subfamily of K2P channels, is opened by intracellular alkalization leading the deprotonation of the K245 residue at the end of the TM4 helix. This charge neutralization of K245 could be sensitive or coupled to the fenestration state. Here, we describe the relationship between the states of the intramembrane fenestrations and K245 residue in TASK-2 channel. By using molecular modeling and simulations, we show that the protonated state of K245 (K245+) favors the open fenestration state and, symmetrically, that the open fenestration state favors the protonated state of the lysine residue. We show that the channel can be completely blocked by Prozac, which is known to induce fenestration opening in TREK-2. K245 protonation and fenestration aperture have an additive effect on the conductance of the channel. The opening of the fenestrations with K245+ increases the entrance of lipids into the selectivity filter, blocking the channel. At the same time, the protonation of K245 introduces electrostatic potential energy barriers to ion entrance. We computed the free energy profiles of ion penetration into the channel in different fenestration and K245 protonation states, to show that the effects of the two transformations are summed up, leading to maximum channel blocking. Estimated rates of ion transport are in qualitative agreement with experimental results and support the hypothesis that the most important barrier for ion transport under K245+ and open fenestration conditions is the entrance of the ions into the channel.

scholarly journals Structural behavior of amphiphilic polyion complexes interacting with saturated lipid membranes investigated by coarse-grained molecular dynamic simulations

RSC Advances ◽  
2020 ◽  
Vol 10 (64) ◽  
pp. 39204-39216
Author(s):  
Daniel G. Angelescu
Keyword(s):  
Lipid Membranes ◽  
Lipid Membrane ◽  
Coarse Grained ◽  
Structural Behavior ◽  
Molecular Dynamic Simulations ◽  
Dynamic Simulations ◽  
Polyelectrolyte Complexes ◽  
Multiblock Copolymer ◽  
Oppositely Charged ◽  
Polyion Complexes

Neutral polyelectrolyte complexes (PECs) made from an amphiphilic multiblock copolymer of type (AnBn)m and an oppositely charged polyion and interacting with a dipalmitoylphosphatidylcholine (DPPC) lipid membrane.

scholarly journals Physical mechanisms of amyloid nucleation on fluid membranes

2019 ◽  
Author(s):  
Johannes Krausser ◽  
Tuomas P. J. Knowles ◽  
Anđela Šarić
Keyword(s):  
Lipid Membranes ◽  
Molecular Mechanisms ◽  
Amyloid Fibrils ◽  
Lipid Membrane ◽  
Coarse Grained ◽  
Coarse Grained Model ◽  
Physical Mechanisms ◽  
Membrane Affinity ◽  
Fluid Membranes ◽  
Protein Membrane

Biological membranes can dramatically accelerate the aggregation of normally soluble protein molecules into amyloid fibrils and alter the fibril morphologies, yet the molecular mechanisms through which this accelerated nucleation takes place are not yet understood. Here, we develop a coarse-grained model to systematically explore the effect that the structural properties of the lipid membrane and the nature of protein-membrane interactions have on the nucleation rates of amyloid fibrils. We identify two physically distinct nucleation pathways and quantify how the membrane fluidity and protein-membrane affinity control the relative importance of those molecular pathways. We find that the membrane’s susceptibility to reshaping and being incorporated into the fibrillar aggregates is a key determinant of its ability to promote protein aggregation. We then characterise the rates and the free energy profile associated to this heterogeneous nucleation process in which the surface itself participates in the aggregate structure. Finally, we compare quantitatively our data to experiments on membrane-catalysed amyloid aggregation of α-synuclein, a protein implicated in Parkinson’s disease that predominately nucleates on membranes. More generally, our results provide a framework for understanding macromolecular aggregation on lipid membranes in a broad biological and biotechnological context.

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