scholarly journals Water Nanoconfined in a Hydrophobic Pore: Molecular Dynamics Simulations of Transmembrane Protein 175 and the Influence of Water Models

ACS Nano ◽  
2021 ◽  
Author(s):  
Charlotte I. Lynch ◽  
Gianni Klesse ◽  
Shanlin Rao ◽  
Stephen J. Tucker ◽  
Mark S. P. Sansom
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Transmembrane Protein ◽  
Hydrophobic Pore ◽  
Influence Of Water ◽  
Water Models ◽  
Dynamics Simulations

Systematic Comparison of the Structural and Dynamic Properties of Commonly Used Water Models for Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Sachini P. Kadaoluwa Pathirannahalage ◽  
Nastaran Meftahi ◽  
Aaron Elbourne ◽  
Alessia C. G. Weiss ◽  
Chris F. McConville ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Dynamic Properties ◽  
Systematic Comparison ◽  
Water Models ◽  
Dynamics Simulations

scholarly journals The Interplay of Cholesterol and Ligand Binding in hTSPO from Classical Molecular Dynamics Simulations

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1250
Author(s):  
Hien T. T. Lai ◽  
Alejandro Giorgetti ◽  
Giulia Rossetti ◽  
Toan T. Nguyen ◽  
Paolo Carloni ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Molecular Dynamics Simulations ◽  
Binding Site ◽  
Transmembrane Protein ◽  
Free Form ◽  
Experimental Investigations ◽  
Terminal Part ◽  
Dynamics Simulations ◽  
Cholesterol Binding

The translocator protein (TSPO) is a 18kDa transmembrane protein, ubiquitously present in human mitochondria. It is overexpressed in tumor cells and at the sites of neuroinflammation, thus representing an important biomarker, as well as a promising drug target. In mammalian TSPO, there are cholesterol–binding motifs, as well as a binding cavity able to accommodate different chemical compounds. Given the lack of structural information for the human protein, we built a model of human (h) TSPO in the apo state and in complex with PK11195, a molecule routinely used in positron emission tomography (PET) for imaging of neuroinflammatory sites. To better understand the interactions of PK11195 and cholesterol with this pharmacologically relevant protein, we ran molecular dynamics simulations of the apo and holo proteins embedded in a model membrane. We found that: (i) PK11195 stabilizes hTSPO structural fold; (ii) PK11195 might enter in the binding site through transmembrane helices I and II of hTSPO; (iii) PK11195 reduces the frequency of cholesterol binding to the lower, N–terminal part of hTSPO in the inner membrane leaflet, while this impact is less pronounced for the upper, C–terminal part in the outer membrane leaflet, where the ligand binding site is located; (iv) very interestingly, cholesterol most frequently binds simultaneously to the so-called CRAC and CARC regions in TM V in the free form (residues L150–X–Y152–X(3)–R156 and R135–X(2)–Y138–X(2)–L141, respectively). However, when the protein is in complex with PK11195, cholesterol binds equally frequently to the CRAC–resembling motif that we observed in TM I (residues L17–X(2)–F20–X(3)–R24) and to CRAC in TM V. We expect that the CRAC–like motif in TM I will be of interest in future experimental investigations. Thus, our MD simulations provide insight into the structural features of hTSPO and the previously unknown interplay between PK11195 and cholesterol interactions with this pharmacologically relevant protein.

scholarly journals Cavity hydration dynamics in cytochrome c oxidase and functional implications

2017 ◽  
Vol 114 (42) ◽  
pp. E8830-E8836 ◽  
Author(s):  
Chang Yun Son ◽  
Arun Yethiraj ◽  
Qiang Cui
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Proton Transfer ◽  
Molecular Dynamics Simulations ◽  
Transmembrane Protein ◽  
Wetting Transition ◽  
Protonation State ◽  
Hydration Level ◽  
Level Change ◽  
Dynamics Simulations

Cytochrome c oxidase (CcO) is a transmembrane protein that uses the free energy of O2 reduction to generate the proton concentration gradient across the membrane. The regulation of competitive proton transfer pathways has been established to be essential to the vectorial transport efficiency of CcO, yet the underlying mechanism at the molecular level remains lacking. Recent studies have highlighted the potential importance of hydration-level change in an internal cavity that connects the proton entrance channel, the site of O2 reduction, and the putative proton exit route. In this work, we use atomistic molecular dynamics simulations to investigate the energetics and timescales associated with the volume fluctuation and hydration-level change in this central cavity. Extensive unrestrained molecular dynamics simulations (accumulatively ∼4 μs) and free energy computations for different chemical states of CcO support a model in which the volume and hydration level of the cavity are regulated by the protonation state of a propionate group of heme a3 and, to a lesser degree, the redox state of heme a and protonation state of Glu286. Markov-state model analysis of ∼2-μs trajectories suggests that hydration-level change occurs on the timescale of 100–200 ns before the proton-loading site is protonated. The computed energetic and kinetic features for the cavity wetting transition suggest that reversible hydration-level change of the cavity can indeed be a key factor that regulates the branching of proton transfer events and therefore contributes to the vectorial efficiency of proton transport.

Molecular dynamics simulations of vapor/liquid coexistence using the nonpolarizable water models

2011 ◽  
Vol 134 (12) ◽  
pp. 124708 ◽  
Author(s):  
Ryuji Sakamaki ◽  
Amadeu K. Sum ◽  
Tetsu Narumi ◽  
Kenji Yasuoka
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Water Models ◽  
Dynamics Simulations ◽  
Vapor Liquid

scholarly journals Accurate Simulations of Lipid Monolayers Require a Water Model With Correct Surface Tension

2021 ◽  
Author(s):  
Carmelo Tempra ◽  
O.H. Samuli Ollila ◽  
Matti Javanainen
Keyword(s):  
Molecular Dynamics ◽  
Surface Tension ◽  
Molecular Dynamics Simulations ◽  
Long Range ◽  
Van Der Waals ◽  
Water Model ◽  
Lipid Monolayers ◽  
Experimental Surface ◽  
Water Models ◽  
Dynamics Simulations

Lipid monolayers provide our lungs and eyes their functionality, and serve as proxy systems in biomembrane research. Therefore, lipid monolayers have been studied intensively also using molecular dynamics simulations, which are able to probe their lateral structure and interactions with, e.g., pharmaceuticals or nanoparticles. However, such simulations have struggled in describing the forces at the air–water interface. Particularly the surface tension of water and long-range van der Waals interactions have been considered critical, but their importance in monolayer simulations has been evaluated only separately. Here we combine the recent C36/LJ-PME lipid force field that in- cludes long-range van der Waals forces with water models that reproduce experimental surface tensions to elucidate the importance of these contributions in monolayer simulations. Our results suggest that a water model with correct surface tension is necessary to reproduce experimental surface pressure–area isotherms and monolayer phase behavior, while standard cutoff-based CHARMM36 lipid model with the 4-point OPC water model still provides the best agreement with experiments. Our results emphasize the importance of using high quality water models in applications and parameter development in molecular dynamics simulations of biomolecules.

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