The overexpression of p21-activated kinase 4 (PAK4) is associated with a variety of cancers. In this paper, the binding modes and inhibitory mechanisms of four 7H-pyrrolo2,3-dpyrimidine competitive ...inhibitors of PAK4 were investigated at the molecular level, mainly using molecular dynamics simulations and binding free energy calculations. The results show that the inhibitors had strong interactions with the hinge region, the β-sheets, and the residues with charged side chains around the 4-substituent. The terminal amino group of the inhibitor 5n was different from the other three, which could cause the enhancement of hydrogen bonds or electrostatic interactions formed with the surrounding residues. Thus, inhibitor 5n had the strongest inhibition capacity. The different halogen atoms on the 2-substituents of the inhibitors 5h, 5g, and 5e caused differences in the positions of the 2-benzene rings and affected the interactions of the hinge region. It also affected to some extent the orientations of the 4-imino groups and consequently their affinities for the surrounding charged residues. The combined results lead to the weakest inhibitory capacity of inhibitor 5e.
The coarse-grained Martini force field is widely used in biomolecular simulations. Here we present the refined model, Martini 3 ( http://cgmartini.nl ), with an improved interaction balance, new bead ...types and expanded ability to include specific interactions representing, for example, hydrogen bonding and electronic polarizability. The updated model allows more accurate predictions of molecular packing and interactions in general, which is exemplified with a vast and diverse set of applications, ranging from oil/water partitioning and miscibility data to complex molecular systems, involving protein-protein and protein-lipid interactions and material science applications as ionic liquids and aedamers.
The set of TXsub.3-TrXsub.2 (T = C, Si, Ge; Tr = B, Al, Ga; X = F, Cl, Br) molecules offers a rather unique opportunity to study both σ-hole and π-hole dimerization on the tetrel and triel ends, ...respectively. According to the molecular electrostatic potential (MEP) distribution, the π-hole extrema (acidic sites) were more intense than their σ-hole counterparts. The molecules owning the most (CXsub.3-AlXsub.2) and least (SiXsub.3-BXsub.2) intense π-holes were chosen to evaluate their capacities to attract one and two HCN molecules (Lewis bases). We discovered that the energetic characteristics of π-hole dimers severely conflict with the monomers MEP pattern since the weakest π-hole monomer forms a dimer characterized by interaction energy compared to those created by the monomers with noticeably greater power in the π-hole region. This outcome is due to the deformation of the weakest π-hole donor. Furthermore, the MEP analysis for monomers in the geometry of respective dimers revealed a “residual π-hole” site that was able to drive second ligand attachment, giving rise to the two “unusual trimers” examined further by the NCI and QTAIM analyses. Apart from them, the π-hole/π-hole and σ-hole/π-hole trimers have also been obtained throughout this study and described using energetic and geometric parameters. The SAPT approach revealed details of the bonding in one of the “unusual trimers”. Finally, Born-Oppenheimer Molecular Dynamics (BOMD) simulations were carried out to investigate the time evolution of the interatomic distances of the studied complexes as well as their stability.
Recent outbreak of Coronavirus disease (COVID-19) pandemic around the world is associated with 'severe acute respiratory syndrome' (SARS-CoV2) in humans. SARS-CoV2 is an enveloped virus and E ...proteins present in them are reported to form ion channels, which is mainly associated with pathogenesis. Thus, there is always a quest to inhibit these ion channels, which in turn may help in controlling diseases caused by SARS-CoV2 in humans. Considering this, in the present study, authors employed computational approaches for studying the structure as well as function of the human 'SARS-CoV2 E' protein as well as its interaction with various phytochemicals. Result obtained revealed that α-helix and loops present in this protein experience random movement under optimal condition, which in turn modulate ion channel activity; thereby aiding the pathogenesis caused via SARS-CoV2 in human and other vertebrates. However, after binding with Belachinal, Macaflavanone E, and Vibsanol B, the random motion of the human 'SARS-CoV2 E' protein gets reduced, this, in turn, inhibits the function of the 'SARS-CoV2 E' protein. It is pertinent to note that two amino acids, namely VAL25 and PHE26, play a key role while interacting with these three phytochemicals. As these three phytochemicals, namely, Belachinal, Macaflavanone E & Vibsanol B, have passed the ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) property as well as 'Lipinski's Rule of 5s', they may be utilized as drugs in controlling disease caused via SARS-COV2, after further investigation.
Communicated by Ramaswamy H. Sarma
In this study, a reasonable 3D structure of enzyme IIC (EIIC) was established using ab initio methods. Curcumin, baicalein and phloretin were screened out from 127,695 natural products based on EIIC ...protein in Staphylococcus aureus (S. aureus) by using the virtual screening technology. The antibacterial assays results confirmed that these three compounds could inhibit S. aureus cell growth. The results of molecular docking, molecular dynamics and molecular mechanics/generalized born surface area calculation indicated that curcumin, baicalein and phloretin mainly bound to Glu275, His231, and Phe359 of EIIC through hydrogen bonds and van der Waals forces to obstruct the transport of glucose-based carbohydrates, and thereby inhibited the carbohydrate metabolism of S. aureus. The steered molecular dynamics analysis revealed the existence of transfer channel in EIIC and illustrated that curcumin, baicalein and phloretin could dissociate from EIIC when pulling force on them. Furthermore, alanine scanning and hydrogen bond occupancy analyses found that Glu275 played an important role in stabilizing EIIC-baicalein/curcumin/phloretin complexes, and 275Glu@OE1 was a stable hydrogen bond acceptor. Therefore, Glu275 may be a hot spot residue that can maintain the stable binding of agents to EIIC, which may be a direction for the development of new drugs against S. aureus.
•Curcumin, baicalein and phloretin were screened out by virtual screening technology.•The compounds can bind to EIIC to hinder sugar intake inhibiting the bacteria growth.•H-bonds and van der Waals forces had contributions to the EIIC-ligand complexes.•When pulling force on these three compounds, they could dissociate from EIIC.
In order to study the interaction between composite photocatalytic material TiOsub.2@LDO and matrix asphalt, the four-component 12 molecular structure model of 70# matrix asphalt was optimized by ...using software Materials Studio 2020, and its heterostructure with TiOsub.2@LDO composite was modeled. The bonding performance between asphalt and composite photocatalytic material was analyzed by interface energization, and the diffusion performance between asphalt and composite photocatalytic material was analyzed from the perspectives of particle movement and Z-direction density. By changing the temperature and other parameters in the simulation process, the change in bonding strength between TiOsub.2@LDO and asphalt was investigated. Through the calculation and analysis of interaction energy, it was found that the adsorption and bonding strength between asphalt and TiOsub.2@LDO were the strongest at 40 °C. At the same time, the diffusion performance was studied, and it was found that the molecular diffusion distribution of TiOsub.2@LDO was more extensive at 60 °C, which laid the foundation for further blending of asphalt and TiOsub.2@LDO. The simulation results show that TiOsub.2@LDO molecules have a certain attraction to asphalt molecules and can modify the matrix asphalt to some extent.
Molecular Dynamics Simulation for All Hollingsworth, Scott A.; Dror, Ron O.
Neuron (Cambridge, Mass.),
09/2018, Volume:
99, Issue:
6
Journal Article
Peer reviewed
Open access
The impact of molecular dynamics (MD) simulations in molecular biology and drug discovery has expanded dramatically in recent years. These simulations capture the behavior of proteins and other ...biomolecules in full atomic detail and at very fine temporal resolution. Major improvements in simulation speed, accuracy, and accessibility, together with the proliferation of experimental structural data, have increased the appeal of biomolecular simulation to experimentalists—a trend particularly noticeable in, although certainly not limited to, neuroscience. Simulations have proven valuable in deciphering functional mechanisms of proteins and other biomolecules, in uncovering the structural basis for disease, and in the design and optimization of small molecules, peptides, and proteins. Here we describe, in practical terms, the types of information MD simulations can provide and the ways in which they typically motivate further experimental work.
Hollingsworth and Dror review modern molecular dynamics (MD) simulations, with an emphasis on how such simulations complement wet-lab experiments. MD simulations capture biomolecular motion in atomic detail and have come into widespread use because of recent technological and scientific advances.
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