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A major concern in the modern cement industry is considering how to minimize the CO2 footprint. Thus, cements based on belite, an impure clinker mineral (CaO)2SiO2 (C2S in cement chemistry notation), which forms at lower temperatures, is a promising solution to develop eco-efficient and sustainable cement-based materials, used in enormous quantities. The slow reactivity of belite plays a critical role, but the dissolution mechanisms and kinetic rates at the atomistic scale are not known completely yet. This work aims to understand the dissolution behavior of different facets of β-C2S providing missing input data and an upscaling modeling approach to connect the atomistic scale to the sub-micro scale. First, a combined ReaxFF and metadynamics-based molecular dynamic approach are applied to compute the atomistic forward reaction rates (RD) of calcium (Ca) and silicate species of (100) facet of β-C2S considering the influence of crystal facets and crystal defects. To minimize the huge number of atomistic events possibilities, a generalized approach is proposed, based on the systematic removal of nearest neighbors' crystal sites. This enables us to tabulate data on the forward reaction rates of most important atomistic scenarios, which are needed as input parameters to implement the Kinetic Monte Carlo (KMC) computational upscaling approach. The reason for the higher reactivity of the (100) facet compared to the (010) is explained. [ABSTRACT FROM AUTHOR]

Molecular dynamics (MD) simulation has been widely used in the field of biomedicine to study the conformational transition of proteins caused by mutation or ligand binding/unbinding. It provides some perspectives those are difficult to find in traditional biochemical or pathological experiments, for example, detailed effects of mutations on protein structure and protein–protein/ligand interaction at the atomic level. In this review, a broad overview on conformation changes and drug discovery by MD simulation is given. We first discuss the preparation of protein structure for MD simulation, which is a key step that determines the accuracy of the simulation. Then, we summarize the applications of commonly used force fields and MD simulations in scientific research. Finally, enhanced sampling methods and common applications of these methods are introduced. In brief, MD simulation is a powerful tool and it can be used to guide experimental study. The combination of MD simulation and experimental techniques is an a priori means to solve the biomedical problems and give a deep understanding on the relationship between protein structure and function. [ABSTRACT FROM AUTHOR]

[Display omitted] • MPXV putative virulence factor is targeted for anti-mpox in silico drug discovery. • Nux-vomica phytochemicals had stable interactions against the virulence protein. • Brincidofovir standard had lowest affinity to MPXV virulence protein. • Nux-vomica phytochemicals had ADMET properties comparable to brincidofovir. • Asn21, Tyr19, Pro17 are key residues in ligand interactions by molecular docking. This study targeted MPXV (mpox virus) virulence factor (MPXV_VF) for anti-mpox drug discovery using Strychnos nux-vomica phytochemicals. Molecular docking showed stronger binding energy of phytochemicals (−7.1–−6.1 kcal/mol) compared to brincidofovir (−5.2–−4.9 kcal/mol). Molecular dynamics simulations authenticated the conformational stability of MPXV_VF-VCN complex. The most potent to inhibit MPXV_VF was VCN that exhibited favourable ADMET profiles comparable to brincidofovir. The metadynamics as a function of distance of Arg85Cα with VCN-C18, and phi Arg85 showed two deepest free energy basins (−129.144 and −109.250 kJ/mol) relative to unbound state. Thus, VCN could be used as main-stream drug candidate for mpox treatment. [ABSTRACT FROM AUTHOR]

Extensive classical and quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations are used to establish the structural features of the O state in bacteriorhodopsin (bR) and its conversion back to the bR ground state. The computed free energy surface is consistent with available experimental data for the kinetics and thermodynamics of the O to bR transition. The simulation results highlight the importance of the proton release group (PRG, consisting of Glu194/204) and the conserved arginine 82 in modulating the hydration level of the protein cavity. In particular, in the O state, deprotonation of the PRG and downward rotation of Arg82 lead to elevated hydration level and a continuous water network that connects the PRG to the protonated Asp85. Proton exchange through this water network is shown by ~0.1-#956;s semiempirical QM/MM free energy simulations to occur through the generation and propagation of a proton hole, which is relayed by Asp212 and stabilized by Arg82. This mechanism provides an explanation for the observation that the D85S mutant of bacteriorhodopsin pumps chloride ions. The electrostatics-hydration coupling mechanism and the involvement of all titration states of water are likely applicable to many biomolecules involved in bioenergetic transduction. [ABSTRACT FROM AUTHOR]

Biomolecular simulations are routinely used in biochemistry and molecular biology research; however, they often fail to match expectations of their impact on pharmaceutical and biotech industry. This is caused by the fact that a vast amount of computer time is required to simulate short episodes from the life of biomolecules. Several approaches have been developed to overcome this obstacle, including application of massively parallel and special purpose computers or non-conventional hardware. Methodological approaches are represented by coarse-grained models and enhanced sampling techniques. These techniques can show how the studied system behaves in long time-scales on the basis of relatively short simulations. This review presents an overview of new simulation approaches, the theory behind enhanced sampling methods and success stories of their applications with a direct impact on biotechnology or drug design. [ABSTRACT FROM AUTHOR]

Abstract: Background: The smoothened (SMO) receptor, one of the Class F G protein coupled receptors (GPCRs), is an essential component of the canonical hedgehog signaling pathway which plays a key role in the regulation of embryonic development in animals. The function of the SMO receptor can be modulated by small-molecule agonists and antagonists, some of which are potential antitumour agents. Understanding the binding mode of an antagonist in the SMO receptor is crucial for the rational design of new antitumour agents. Methods: Molecular dynamics (MD) simulation and dynamical network analysis are used to study the dynamical structural features of SMO receptor. Metadynamics simulation and free energy calculation are employed to explore the binding mechanism between the antagonist and SMO receptor. Results: The MD simulation results and dynamical network analysis show that the conserved KTXXXW motif in helix VIII has strong interaction with helix I. The α-helical extension of transmembrane 6 (TM6) is detected as part of the ligand-binding pocket and dissociation pathway of the antagonist. The metadynamics simulation results illustrate the binding mechanism of the antagonist in the pocket of SMO receptor, and free energy calculation shows the antagonist needs to overcome about 38kcal/mol of energy barrier to leave the binding pocket of SMO receptor. Conclusions: The unusually long TM6 plays an important role on the binding behavior of the antagonist in the pocket of SMO receptor. General significance: The results can not only profile the binding mechanism between the antagonist and Class F GPCRs, but also supply the useful information for the rational design of a more potential small molecule antagonist bound to SMO receptor. [Copyright &y& Elsevier]

The current contribution proposes a multi-scale bridging modeling approach for the dissolution of crystals to connect the atomistic scale to the (sub-) micro-scale. This is demonstrated in the example of dissolution of portlandite, as a relatively simple benchmarking example for cementitious materials. Moreover, dissolution kinetics is also important for other industrial processes, e.g., acid gas absorption and pH control. In this work, the biased molecular dynamics (metadynamics) coupled with reactive force field is employed to calculate the reaction path as a free energy surface of calcium dissolution at 298 K in water from the different crystal facets of portlandite. It is also explained why the reactivity of the (010), (100), and (1 1 ¯ 0) crystal facet is higher compared to the (001) facet. In addition, the influence of neighboring Ca crystal sites arrangements on the atomistic dissolution rates is explained as necessary scenarios for the upscaling. The calculated rate constants of all atomistic reaction scenarios provided an input catalog ready to be used in an upscaling kinetic Monte Carlo (KMC) approach. [ABSTRACT FROM AUTHOR]

Abstract: Modelling of carbohydrate conformations is a challenging task for force field developers. Three carbohydrate force fields, namely GLYCAM06, GROMOS 45a4 and OPLS were evaluated. Free energies of different ring conformations of β-d-glucopyranose were calculated using metadynamics in vacuum as well as in explicitly modelled water. All three force fields model the 4 C 1 conformation as the most stable by at least 6kJ/mol, as compared to other conformations. Interconversion from the 4 C 1 to any other conformation is associated with a barrier of no lower than 26kJ/mol. The free energy surface calculated in the GLYCAM06 force field is in remarkably good agreement with the recent Car-Parrinello metadynamics study. The effect of a water environment is relatively low and analogous in all tested force fields. Namely, the presence of water stabilizes the upper-left (3,O B) versus bottom-right (B 3,O) area of Stoddard’s plot, relative to the situation in vacuum. Comparison of free and potential surfaces is also provided for vacuum calculations. [Copyright &y& Elsevier]

Abstract: Homology modeling of unknown proteins is based on the assumption that highly similar sequences are likely to share the same fold. However, this does not provide any information on the stability of a given fold, which is ultimately determined by the subtle interplay of enthalpic and entropic contributions. Herein it is shown that ab initio atomistic simulations can be used to predict the effect of point mutations on the stability of a protein fold. The calculations indicate that the fold stabilities of two proteins of similar sequence and identical fold, the villin and advillin C-terminal headpiece fragments, are different and that the same P62A point mutation has a dramatic effect on the fold of villin but a minor one on that of advillin. These predictions were subsequently validated by NMR and CD experiments. [Copyright &y& Elsevier]

Since using nanoscale structures as drug delivery systems overcome issues of drug solubility during cell targeting, molecular dynamics (MD) simulation has been applied to get precise on the capability of Graphydine oxide (GDYO) nanosheet to load Idarubicin (IDR) drug. It is found the strong attraction between IDR and GDYO originates from the significant decreasing of the vdW interaction energy which reveals the GDYO is a suitable carrier for delivery of Idarubicin therapeutic agent. It is observed IDR drug non-covalently lands on the GDYO surface through the hydrophobic π-π stacking interaction. Well-tempered metadynamics simulation also provides the binding free energy profile of IDR drug during the adsorption on the nanosheet surface. Furthermore, mechanism of biomembrane penetration of Graphydine oxide nanosheet loaded with IDR anticancer drug is investigated by MD simulation. The results show that the diffusion of IDR-GDYO complex above the POPC bilayer occurs without persist physical contacts between GDYO and POPC bilayer at the initial time of simulation. Detailed geometrical considerations reveal IDR adsorbed molecule still remains in conjugation with Graphydine oxide in the membrane/water interface until the end of simulation time. In other words, the adsorbed biomolecule with assistance of Graphydine oxide as a vehicle approaches to the membrane surface. • The vdW interaction energy is the main attractive contact during IDR adsorption on GDYO nanosheet. • GDYO as a suitable vehicle is able to transport and stabilize IDR molecule at the near cell membrane. [ABSTRACT FROM AUTHOR]

Early hydration of tricalcium silicate (C3S) has received great attention over the years due to the increased use of composite cement with a reduced number of clinker phases, especially the addition of what should be very reactive C3S to guarantee early strength. Although many mechanisms have been proposed, the dissolution of polygonal C3S at the material interface is not yet fully understood. Over the last decade, computational methods have been developed to describe the reaction in the cementitious system. This paper proposes an atomistic insight into the early hydration and the dissolution mechanism of calcium from different crystalline planes of C3S using reactive force field (ReaxFF) combined with metadynamics (metaD). The reactivity and thermodynamic stability of different crystal planes were calculated from the dissolution profile of calcium during hydration at 298 K. The simulation results, clearly describe the higher reactivity of ( 0 1 ¯ 1 ¯ ), (011), (100), and (1 ¯ 00) surfaces of C3S due to the strong interaction with the water, whereas, the dissolution profile explains the lower reactivity of ( 1 ¯ 1 ¯ 0 ), (110), ( 0 1 ¯ 0 ) and the effect of water tessellation on the (001), (010) planes. [ABSTRACT FROM AUTHOR]