Research

12 pages, 3145 KiB

Open AccessArticle

Protonation Equilibrium in the Active Site of the Photoactive Yellow Protein

by Pablo Campomanes and Stefano Vanni

Molecules 2021, 26(7), 2025; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26072025 - 02 Apr 2021

Viewed by 1901

The role and existence of low-barrier hydrogen bonds (LBHBs) in enzymatic and protein activity has been largely debated. An interesting case is that of the photoactive yellow protein (PYP). In this protein, two short HBs adjacent to the chromophore, p-coumaric acid (pCA), [...] Read more.

The role and existence of low-barrier hydrogen bonds (LBHBs) in enzymatic and protein activity has been largely debated. An interesting case is that of the photoactive yellow protein (PYP). In this protein, two short HBs adjacent to the chromophore, p-coumaric acid (pCA), have been identified by X-ray and neutron diffraction experiments. However, there is a lack of agreement on the chemical nature of these H-bond interactions. Additionally, no consensus has been reached on the presence of LBHBs in the active site of the protein, despite various experimental and theoretical studies having been carried out to investigate this issue. In this work, we perform a computational study that combines classical and density functional theory (DFT)-based quantum mechanical/molecular mechanical (QM/MM) simulations to shed light onto this controversy. Furthermore, we aim to deepen our understanding of the chemical nature and dynamics of the protons involved in the two short hydrogen bonds that, in the dark state of PYP, connect pCA with the two binding pocket residues (E46 and Y42). Our results support the existence of a strong LBHB between pCA and E46, with the H fully delocalized and shared between both the carboxylic oxygen of E46 and the phenolic oxygen of pCA. Additionally, our findings suggest that the pCA interaction with Y42 can be suitably described as a typical short ionic H-bond of moderate strength that is fully localized on the phenolic oxygen of Y42. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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12 pages, 1341 KiB

Open AccessArticle

CGMD Platform: Integrated Web Servers for the Preparation, Running, and Analysis of Coarse-Grained Molecular Dynamics Simulations

by Alessandro Marchetto, Zeineb Si Chaib, Carlo Alberto Rossi, Rui Ribeiro, Sergio Pantano, Giulia Rossetti and Alejandro Giorgetti

Molecules 2020, 25(24), 5934; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25245934 - 15 Dec 2020

Cited by 13 | Viewed by 6560

Abstract

Advances in coarse-grained molecular dynamics (CGMD) simulations have extended the use of computational studies on biological macromolecules and their complexes, as well as the interactions of membrane protein and lipid complexes at a reduced level of representation, allowing longer and larger molecular dynamics [...] Read more.

Advances in coarse-grained molecular dynamics (CGMD) simulations have extended the use of computational studies on biological macromolecules and their complexes, as well as the interactions of membrane protein and lipid complexes at a reduced level of representation, allowing longer and larger molecular dynamics simulations. Here, we present a computational platform dedicated to the preparation, running, and analysis of CGMD simulations. The platform is built on a completely revisited version of our Martini coarsE gRained MembrAne proteIn Dynamics (MERMAID) web server, and it integrates this with other three dedicated services. In its current version, the platform expands the existing implementation of the Martini force field for membrane proteins to also allow the simulation of soluble proteins using the Martini and the SIRAH force fields. Moreover, it offers an automated protocol for carrying out the backmapping of the coarse-grained description of the system into an atomistic one. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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16 pages, 1414 KiB

Open AccessArticle

Combining EXAFS and Computer Simulations to Refine the Structural Description of Actinyls in Water

by Sergio Pérez-Conesa, José M. Martínez, Rafael R. Pappalardo and Enrique Sánchez Marcos

Molecules 2020, 25(22), 5250; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25225250 - 11 Nov 2020

Cited by 2 | Viewed by 2036

Abstract

EXAFS spectroscopy is one of the most used techniques to solve the structure of actinoid solutions. In this work a systematic analysis of the EXAFS spectra of four actinyl cations, [UO₂]²⁺, [NpO₂]²⁺, [NpO₂] [...] Read more.

EXAFS spectroscopy is one of the most used techniques to solve the structure of actinoid solutions. In this work a systematic analysis of the EXAFS spectra of four actinyl cations, [UO₂]²⁺, [NpO₂]²⁺, [NpO₂]⁺ and [PuO₂]²⁺ has been carried out by comparing experimental results with theoretical spectra. These were obtained by averaging individual contributions from snapshots taken from classical Molecular Dynamics simulations which employed a recently developed [AnO₂]^2+/+ –H₂O force field based on the hydrated ion model using a quantum-mechanical (B3LYP) potential energy surface. Analysis of the complex EXAFS signal shows that both An-O

_{yl}

and An-O

_{W}

single scattering paths as well as multiple scattering ones involving [AnO₂]^+/2+ molecular cation and first-shell water molecules are mixed up all together to produce a very complex signal. Simulated EXAFS from the B3LYP force field are in reasonable agreement for some of the cases studied, although the k= 6–8 Å

^{- 1}

region is hard to be reproduced theoretically. Except uranyl, all studied actinyls are open-shell electron configurations, therefore it has been investigated how simulated EXAFS spectra are affected by minute changes of An-O bond distances produced by the inclusion of static and dynamic electron correlation in the quantum mechanical calculations. A [NpO₂]⁺−H₂O force field based on a NEVPT2 potential energy surface has been developed. The small structural changes incorporated by the electron correlation on the actinyl aqua ion geometry, typically smaller than 0.07 Å, leads to improve the simulated spectrum with respect to that obtained from the B3LYP force field. For the other open-shell actinyls, [NpO₂]²⁺ and [PuO₂]²⁺, a simplified strategy has been adopted to improve the simulated EXAFS spectrum. It is computed taking as reference structure the NEVPT2 optimized geometry and including the DW factors of their corresponding MD simulations employing the B3LYP force field. A better agreement between the experimental and the simulated EXAFS spectra is found, confirming the a priori guess that the inclusion of dynamic and static correlation refine the structural description of the open-shell actinyl aqua ions. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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16 pages, 4801 KiB

Open AccessArticle

Out of Sight, Out of Mind: The Effect of the Equilibration Protocol on the Structural Ensembles of Charged Glycolipid Bilayers

by Andresa Messias, Denys E. S. Santos, Frederico J. S. Pontes, Filipe S. Lima and Thereza A. Soares

Molecules 2020, 25(21), 5120; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25215120 - 04 Nov 2020

Cited by 8 | Viewed by 2666

Abstract

Molecular dynamics (MD) simulations represent an essential tool in the toolbox of modern chemistry, enabling the prediction of experimental observables for a variety of chemical systems and processes and majorly impacting the study of biological membranes. However, the chemical diversity of complex lipids [...] Read more.

Molecular dynamics (MD) simulations represent an essential tool in the toolbox of modern chemistry, enabling the prediction of experimental observables for a variety of chemical systems and processes and majorly impacting the study of biological membranes. However, the chemical diversity of complex lipids beyond phospholipids brings new challenges to well-established protocols used in MD simulations of soft matter and requires continuous assessment to ensure simulation reproducibility and minimize unphysical behavior. Lipopolysaccharides (LPS) are highly charged glycolipids whose aggregation in a lamellar arrangement requires the binding of numerous cations to oppositely charged groups deep inside the membrane. The delicate balance between the fully hydrated carbohydrate region and the smaller hydrophobic core makes LPS membranes very sensitive to the choice of equilibration protocol. In this work, we show that the protocol successfully used to equilibrate phospholipid bilayers when applied to complex lipopolysaccharide membranes occasionally leads to a small expansion of the simulation box very early in the equilibration phase. Although the use of a barostat algorithm controls the system dimension and particle distances according to the target pressure, fluctuation in the fleeting pressure occasionally enables a few water molecules to trickle into the hydrophobic region of the membrane, with spurious solvent buildup. We show that this effect stems from the initial steps of NPT equilibration, where initial pressure can be fairly high. This can be solved with the use of a stepwise-thermalization NVT/NPT protocol, as demonstrated for atomistic MD simulations of LPS/DPPE and lipid-A membranes in the presence of different salts using an extension of the GROMOS forcefield within the GROMACS software. This equilibration protocol should be standard procedure for the generation of consistent structural ensembles of charged glycolipids starting from atomic coordinates not previously pre-equilibrated. Although different ways to deal with this issue can be envisioned, we investigated one alternative that could be readily available in major MD engines with general users in mind. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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18 pages, 20550 KiB

Open AccessArticle

Expansion of Intrinsically Disordered Proteins Increases the Range of Stability of Liquid–Liquid Phase Separation

by Adiran Garaizar, Ignacio Sanchez-Burgos, Rosana Collepardo-Guevara and Jorge R. Espinosa

Molecules 2020, 25(20), 4705; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25204705 - 15 Oct 2020

Cited by 34 | Viewed by 5200

Abstract

Proteins containing intrinsically disordered regions (IDRs) are ubiquitous within biomolecular condensates, which are liquid-like compartments within cells formed through liquid–liquid phase separation (LLPS). The sequence of amino acids of a protein encodes its phase behaviour, not only by establishing the patterning and chemical [...] Read more.

Proteins containing intrinsically disordered regions (IDRs) are ubiquitous within biomolecular condensates, which are liquid-like compartments within cells formed through liquid–liquid phase separation (LLPS). The sequence of amino acids of a protein encodes its phase behaviour, not only by establishing the patterning and chemical nature (e.g., hydrophobic, polar, charged) of the various binding sites that facilitate multivalent interactions, but also by dictating the protein conformational dynamics. Besides behaving as random coils, IDRs can exhibit a wide-range of structural behaviours, including conformational switching, where they transition between alternate conformational ensembles. Using Molecular Dynamics simulations of a minimal coarse-grained model for IDRs, we show that the role of protein conformation has a non-trivial effect in the liquid–liquid phase behaviour of IDRs. When an IDR transitions to a conformational ensemble enriched in disordered extended states, LLPS is enhanced. In contrast, IDRs that switch to ensembles that preferentially sample more compact and structured states show inhibited LLPS. This occurs because extended and disordered protein conformations facilitate LLPS-stabilising multivalent protein–protein interactions by reducing steric hindrance; thereby, such conformations maximize the molecular connectivity of the condensed liquid network. Extended protein configurations promote phase separation regardless of whether LLPS is driven by homotypic and/or heterotypic protein–protein interactions. This study sheds light on the link between the dynamic conformational plasticity of IDRs and their liquid–liquid phase behaviour. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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18 pages, 5803 KiB

Open AccessArticle

Impact of Cholesterol on the Stability of Monomeric and Dimeric Forms of the Translocator Protein TSPO: A Molecular Simulation Study

by Zeineb Si Chaib, Alessandro Marchetto, Klevia Dishnica, Paolo Carloni, Alejandro Giorgetti and Giulia Rossetti

Molecules 2020, 25(18), 4299; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25184299 - 19 Sep 2020

Cited by 6 | Viewed by 2934

Abstract

The translocator protein (TSPO) is a transmembrane protein present across the three domains of life. Its functional quaternary structure consists of one or more subunits. In mice, the dimer-to-monomer equilibrium is shifted in vitro towards the monomer by adding cholesterol, a natural component [...] Read more.

The translocator protein (TSPO) is a transmembrane protein present across the three domains of life. Its functional quaternary structure consists of one or more subunits. In mice, the dimer-to-monomer equilibrium is shifted in vitro towards the monomer by adding cholesterol, a natural component of mammalian membranes. Here, we present a coarse-grained molecular dynamics study on the mouse protein in the presence of a physiological content and of an excess of cholesterol. The latter turns out to weaken the interfaces of the dimer by clusterizing mostly at the inter-monomeric space and pushing the contact residues apart. It also increases the compactness and the rigidity of the monomer. These two factors might play a role for the experimentally observed incremented stability of the monomeric form with increased content of cholesterol. Comparison with simulations on bacterial proteins suggests that the effect of cholesterol is much less pronounced for the latter than for the mouse protein. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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19 pages, 9056 KiB

Open AccessArticle

Construction of Molecular Model and Adsorption of Collectors on Bulianta Coal

by He Zhang, Peng Xi, Qiming Zhuo and Wenli Liu

Molecules 2020, 25(17), 4030; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25174030 - 03 Sep 2020

Cited by 17 | Viewed by 2712

Abstract

To study the effects of different oxygen functional groups on the quality of flotation clean low-rank coal, two kinds of collectors with different oxygen-containing functional groups, methyl laurate, and dodecanol, were selected and their flotation behaviors were investigated. The Bulianta coal was the [...] Read more.

To study the effects of different oxygen functional groups on the quality of flotation clean low-rank coal, two kinds of collectors with different oxygen-containing functional groups, methyl laurate, and dodecanol, were selected and their flotation behaviors were investigated. The Bulianta coal was the typical sub-bituminous coal in China, and the coal molecular model of which was constructed based on proximate analysis, ultimate analysis, ¹³C-NMR, and XPS. The chemical structure model of the coal molecule was optimized, and the periodic boundary condition was added via the method of molecular dynamics methods. The different combined systems formed by collectors, water, and a model surface of Bulianta coal have been studied using molecular dynamics simulation. The simulation results of dodecanol and methyl laurate on the surface of Bulianta coal show that dodecanol molecules are not evenly adsorbed on the surface of coal, and have higher adsorption capacity near carboxyl and hydroxyl groups, but less adsorption capacity near carbonyl and ether bonds. Methyl laurate can completely cover the oxygen-containing functional groups on the coal surface. Compared with dodecanol, methyl laurate can effectively improve the hydrophobicity of the Bulianta coal surface, which is consistent with the results of the XPS test and the flotation test. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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14 pages, 3894 KiB

Open AccessArticle

Phase Transition of Ice at High Pressures and Low Temperatures

by Jinjin Xu, Jinfeng Liu, Jinyun Liu, Wenxin Hu, Xiao He and Jinjin Li

Molecules 2020, 25(3), 486; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25030486 - 23 Jan 2020

Cited by 3 | Viewed by 4311

Abstract

The behavior of ice under extreme conditions undergoes the change of intermolecular binding patterns and leads to the structural phase transitions, which are needed for modeling the convection and internal structure of the giant planets and moons of the solar system as well [...] Read more.

The behavior of ice under extreme conditions undergoes the change of intermolecular binding patterns and leads to the structural phase transitions, which are needed for modeling the convection and internal structure of the giant planets and moons of the solar system as well as H2O-rich exoplanets. Such extreme conditions limit the structural explorations in laboratory but open a door for the theoretical study. The ice phases IX and XIII are located in the high pressure and low temperature region of the phase diagram. However, to the best of our knowledge, the phase transition boundary between these two phases is still not clear. In this work, based on the second-order Møller–Plesset perturbation (MP2) theory, we theoretically investigate the ice phases IX and XIII and predict their structures, vibrational spectra and Gibbs free energies at various extreme conditions, and for the first time confirm that the phase transition from ice IX to XIII can occur around 0.30 GPa and 154 K. The proposed work, taking into account the many-body electrostatic effect and the dispersion interactions from the first principles, opens up the possibility of completing the ice phase diagram and provides an efficient method to explore new phases of molecular crystals. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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