Combined Molecular Dynamics Research Articles

Path separation of dissipation-corrected targeted molecular dynamics simulations of protein-ligand unbinding.

Protein-ligand (un)binding simulations are a recent focus of biased molecular dynamics simulations. Such binding and unbinding can occur via different pathways in and out of a binding site. Here, we present a theoretical framework on how to compute kinetics along separate paths and on how to combine the path-specific rates into global binding and unbinding rates for comparison with experimental results. Using dissipation-corrected targeted molecular dynamics in combination with temperature-boosted Langevin equation simulations [S. Wolf et al., Nat. Commun. 11, 2918 (2020)] applied to a two-dimensional model and the trypsin-benzamidine complex as test systems, we assess the robustness of the procedure and discuss the aspects of its practical applicability to predict multisecond kinetics of complex biomolecular systems.

Unraveling the connection between calreticulin and myeloproliferative neoplasms via calcium signaling.

Mutations in the form of insertions and deletions (INDEL) in the calreticulin gene lead to essential thrombocythemia (ET) which is characterized by the formation of thrombosis. However, the connection between calreticulin INDEL and ET remains largely elusive. Through combined molecular dynamics simulation, clustered regularly interspaced short palindromic repeats (CRISPR) and calcium imaging studies on the wild type and mutated isoforms of calreticulin, the mechanism underlying the calreticulin INDEL induced ET was investigated at the molecular level. Our results demonstrate that mutations in exon-9 could lead to significant conformational variations of calreticulin structure and thereby reducing its interaction with calcium ions due to decreased electrostatic contributions. The consequence of mutations on calreticulin's structural integrity was revealed by identifying the key residues and their roles in calcium binding. Furthermore, mutations implemented by CRISPR-Cas9 in exon-9 showed diminished calcium signaling in HEK-293T cells, which agree well with our in-silico findings. The current study might help in understanding the variations of molecular interactions between calreticulin's exon-9 and calcium ions during physiological and pathological conditions. The results might also provide useful information for designing novel therapeutic approaches targeting ET.

Behaviors of a Polymer Chain in Channels: From Zimm to Rouse Dynamics

The effects of confinement and hydrodynamic interactions on single-chain diffusion behaviors are studied by using a combination of molecular dynamics and multiparticle collision dynamics simulations. For polymers in free space, the simulation results showed that the diffusion coefficient D∞ for long chains scales with the chain length N as D∞ ∼ N–ν (ν = 0.588), consistent with the Zimm dynamics, but it deviates from the Zimm dynamics for short chains. For polymers confined in channels with width H, the diffusion coefficient is found to follow two different scaling relations. The observed behaviors could be understood by introducing a microscopic hydrodynamic length ξh, below which the overall effect of hydrodynamic interactions becomes less important. For a confined chain, the diffusion behavior exhibits a crossover from Zimm (nondraining) to Rouse (free draining) dynamics as the channel size H decreases. When H is larger than ξh, the confinement experienced by the polymer chain is weak and the diffusion coefficient scales as D ∼ H0.7, in accordance with the prediction of blob theory; when H is smaller than ξh, D becomes independent of H, implying a free draining condition. A general analytical expression of D is derived by extending the partially permeable sphere model to the blob scale, which gives a quantitative description of the transition from Zimm to Rouse dynamics as H decreases.

Understanding the formation of surface relief gratings in azopolymers: A combined molecular dynamics and experimental study.

The formation of surface relief gratings in thin azopolymeric films is investigated using atomistic molecular dynamics simulations and compared to experimental results for the specific case of poly-disperse-orange3-methyl-methacrylate. For this purpose, the film is illuminated with a light pattern of alternating bright and dark stripes in both cases. The simulations use a molecular mechanics switching potential to explicitly describe the photoisomerization dynamics between the E and Z isomers of the azo-units and take into account the orientation of the transition dipole moment with respect to the light polarization. Local heating and elevation of the illuminated regions with the subsequent movement of molecules into the neighboring dark regions are observed. This leads to the formation of valleys in the bright areas after re-cooling and is independent of the polarization direction. To verify these observations experimentally, the azopolymer film is illuminated with bright stripes of varying width using a spatial light modulator. Atomic force microscopy images confirm that the elevated areas correspond to the previously dark areas. In the experiment, the polarization of the incident light makes only a small difference since tiny grain-like structures form in the valleys only when the polarization is parallel to the stripes.

The prediction and assessment of properties for high energy density fuel – Adamantane derivatives: The combined DFT and molecular dynamics simulation

The structures of high-energy–density fuel are significant factors to influence property, which in turn determines the flight distance and payload of vehicles. The density functional theory and molecular dynamics simulation are employed to predict properties of adamantane derivatives, and explore the effect of structure with the different substitutes and the isomers on properties including density, net heat value, specific impulse, thermal and oxidation stability. For adamantane derivatives with different substitutes, the C/H ratio is treated as the descriptors of density and net heating value. While the number of secondary carbon atom attached by side chains and the gap between HOMO and LUMO are viewed as the descriptors of density and volumetric net heating value for isomers, respectively. Based on the above descriptor, the structures with superior properties are obtained for ethyladamantane, propyladamantane and butyladamantane. The structure of pentyladamantane with excellent properties (2c-ethyl-2t,4c,4t-trimethyladamantane) is predicted due to resembling structure of adamantane derivatives with preferable properties. The thermal and oxidation stability of 2c,2t-dimethyladamantane, 2c-ethyl-2t-methyladamantane, 2c,2t-diethyladamantane and 2c-ethyl-2t,4c,4t-trimethyladamantane with superior properties is close to tetrahydro-dicyclopentadiene meeting requirement of aircraft. Therefore, the guidance, that predicts, screens and assesses the structure and property of adamantane derivatives, is provided in this study by defining descriptors.

Species Distribution During Solid Electrolyte Interphase Formation on Lithium Using MD/DFT-Parameterized Kinetic Monte Carlo Simulations

Lithium metal batteries are one of the promising technologies for future energy storage. One open challenge is the generation of a stable and well performing Solid Electrolyte Interphase (SEI) between lithium metal and electrolyte. Understanding the complex interaction of reactions at the lithium surface and the resulting SEI is crucial for knowledge-driven improvement of the SEI. This study reveals the internal species distribution and geometrical aspects of the native SEI during formation by model-based analysis. To achieve this, a combination of molecular dynamics, density functional theory, and stand-alone 3D-kinetic Monte Carlo simulations is used. The kinetic Monte Carlo model determines the SEI growth features over a long time and length scale so that the SEI can be analyzed quantitatively. The simulation confirms the frequently postulated layered SEI structure arising from the decomposition of an ethylene carbonate/lithium hexafluorophosphate (2 M) electrolyte with lithium metal. These layers are not clearly separated, which is contrary to what is often reported. The gradient distribution of the species within the SEI therefore corresponds to a partly mosaic structured SEI at the borders of the layers. At the lithium surface, an inorganic layer of lithium fluoride and then lithium carbonate is observed, followed by an organic, more porous SEI layer consisting of lithium ethylene dicarbonate. Simulations further reveal the strong prevalence of corrosion processes of the metal, which provide more than 99% of the lithium for the SEI reaction processes. The salt contributes less than 1% to the SEI formation. Additionally, SEI formation below and above the initial interface was observable. The here presented novel modeling approach allows an unprecedented in-depth analysis of processes during native SEI formation that can be used to improve design for high battery performance and durability.

Unveiling the compressive behavior of Fe2Ni2CrAl high entropy alloy: A combined molecular dynamics and finite element study

Unveiling the compressive behavior of Fe2Ni2CrAl high entropy alloy: A combined molecular dynamics and finite element study

Co-Assembly of Carbon Nanotube Porins into Biomimetic Peptoid Membranes.

Robust and cost-effective membrane-based separations are essential to solving many global crises, such as the lack of clean water. Even though the current polymer-based membranes are widely used for separations, their performance and precision can be enhanced by using a biomimetic membrane architecture that consists of highly permeable and selective channels embedded in a universal membrane matrix. Researchers have shown that artificial water and ion channels, such as carbon nanotube porins (CNTPs), embedded in lipid membranes can deliver strong separation performance. However, their applications are limited by the relative fragility and low stability of the lipid matrix. In this work,wedemonstrate that CNTPs can co-assemble into twodimension(2D) peptoid membrane nanosheets, opening up a way to produce highly programmable synthetic membranes with superior crystallinity and robustness. A combination of molecular dynamics (MD) simulations, Ramanspectroscopy, X-ray diffraction(XRD), and atomicforcemicroscopy(AFM) measurements to verify the co-assembly of CNTP and peptoids are used and show that it does not disrupt peptoid monomer packing within the membrane. These results provide a new option for designing affordable artificial membranes and highly robust nanoporous solids.

HNRNPA2B1 as a potential therapeutic target for thymic epithelial tumor recurrence: An integrative network analysis

Thymic epithelial tumors (TETs) are rare malignant tumors, and the molecular mechanisms of both primary and recurrent TETs are poorly understood. Here we established comprehensive proteomic signatures of 15 tumors (5 recurrent and 10 non-recurrent) and 15 pair wised tumor adjacent normal tissues. We then proposed an integrative network approach for studying the proteomics data by constructing protein-protein interaction networks based on differentially expressed proteins and a machine learning-based score, followed by network modular analysis, functional enrichment annotation and shortest path inference analysis. Network modular analysis revealed that primary and recurrent TETs shared certain common molecular mechanisms, including a spliceosome module consisting of RNA splicing and RNA processing, but the recurrent TET was specifically related to the ribosome pathway. Applying the shortest path inference to the collected seed gene module identified that the ribonucleoprotein hnRNPA2B1 probably serves as a potential target for recurrent TET therapy. The drug repositioning combined molecular dynamics simulations suggested that the compound ergotamine could potentially act as a repurposing drug to treat recurrent TETs by targeting hnRNPA2B1. Our study demonstrates the value of integrative network analysis to understand proteotype robustness and its relationships with genotype, and provides hits for further research on cancer therapeutics.

Effect of hydrostatic strain on the thermal conductivity of β-SiC: A combined molecular dynamics and lattice dynamics investigation

Effect of hydrostatic strain on the thermal conductivity of β-SiC: A combined molecular dynamics and lattice dynamics investigation

Computational mutation prediction to enhance or recover enzymatic activity.

Atomistic computational simulations have become a useful tool for biomolecular research. These tools are now becoming sufficiently accurate to predict single point mutations that can enhance or recover enzymatic activity. In this talk I will present the use of computational approaches to perform these predictions, and examples coupled with experimental validation. Two examples of applications of these methods to DNA transaction enzymes will be discussed. The first example involves an enzyme from the APOBEC3 family, which are host restriction factors that inhibit lentiviruses, such as HIV-1. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and the Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Using a combination of molecular dynamics (MD), direct coupling analysis (DCA) and experimental techniques we have investigated the key residues for antivirala ctivities. Overall, our results determine the basis for why rhA3C is less active than human A3C and establish the amino acid network for dimerization and increased activity. The second example involves the methyltransferase (MTase) from Mycoplasma penetrans, which has recently been shown to synthesize the modified nucleotide 5-carboxymethylcytosine (5cxmC), formed as a trace byproduct of cytidine methylation by M.MpeI with the secondary metabolite carboxy-S-adenosyl-L-methionine (CxSAM) in place of the normal reaction cofactor, SAM. The use of computational simulations to investigate this new selectivity and predict additional mutations to enhance this new function, and experimental confirmation of these predictions will be presented and discussed.

Predicting the mechanism of actions of capsid assembly modulators from a combination of molecular dynamics and machine learning.

Interfering with the self-assembly of viral nucleocapsids is a recent and effective approach in the development of novel antivirals. Capsid assembly modulators (CAMs) targeting hepatitis B virus (HBV) have two classes. They can target the virus by either accelerating nucleocapsid assembly or misdirecting it into non-capsid-like particles. In our previous work, molecular dynamics simulations were used to study early nucleocapsid assembly intermediates, such as tetramers and hexamers of the core protein Cp149 with and without bound CAMs. We observed distinct conformations of these intermediates, depending on whether the bound CAM accelerates or misdirects assembly. Here, we have developed and tested several machine learning models in order to distinguish between apo-tetramer structures and those bound to accelerating or misdirecting CAMs. Models based on tertiary structural properties of the capsid protein tetramers and their inter-dimer orientation, as well as models based on direct and inverse contact distances between protein residues, were investigated. The models distinguished the apo states and the two CAM-bound states with very high accuracy. Furthermore, tertiary structure models and residue distance models highlighted different tetramer regions as important for classification. Our models can be used to better understand structural transitions that govern nucleocapsid assembly as well as for selection of structures from molecular dynamics simulations for subsequent docking.

Aggregation and construction mechanisms of microbial extracellular polymeric substances with the presence of different multivalent cations: Molecular dynamic simulation and experimental verification

Interactions between cations and extracellular polymeric substances (EPS) play an important role in the formation of microbial aggregates and have key effects on the physical properties of activated sludge across wastewater and sludge treatment process. Here, a molecular model of EPS cluster in activated sludge was constructed and simulated by molecular dynamics (MD) to probe the structural properties of EPS and the interaction between EPS and prevalent multivalent cations (Ca2+, Mg2+, Al3+). Then the predicted changes in physical properties were validated against the dynamic light scattering, XAD resin fractionation and rheology test. The binding dynamics and interactions mechanisms between multivalent cations and EPS functional groups were further investigated using MD in combination with spectroscopic analysis. Results suggest that biopolymers are originally aggregated by electrostatic and intermolecular interactions forming dynamic clusters with negatively charged surface functional groups, which induced electrostatic repulsion preventing further agglomeration of biopolymer clusters. In the presence of multivalent cations, surface polar functional groups in biopolymers are connected, causing the rearrangement of EPS molecular conformation that forms larger and denser agglomerates. Reduced solvent accessible surface area, enhanced hydrophobicity, and increased binding free energy lead to a strong gel-like network of EPS. Ca2+ and Al3+ predominantly interact with functional groups in polysaccharides, promoting agglomeration of macromolecules. In contrast, Mg2+ and Al3+ disrupted the secondary structure of proteins, exposing hydrophobic interaction sites. Al3+ can better agglomerate biopolymers with its higher positive charge and shorter coordination distance as compared to Ca2+ and Mg2+, but compromised by the effect of hydration. This work offers a novel approach to explore the construction and molecular aggregation of EPS, enriching the theoretical basis for optimization of wastewater and sludge treatment.

On the potentials of sialic acid derivatives as inhibitors for the mumps virus: A molecular dynamics and quantum chemistry investigation

Mumps virus is an infectious pathogen causing major health problems for humans such as encephalitis, orchitis, and parotitis. Therefore, designing an inhibitor for this virus is of great medical and public health importance. With this goal in mind, we investigate the affinity of different sialic acid-based compounds (ligands) against the hemagglutinin-neuraminidase (HN) protein of the mumps virus, using a combination of molecular dynamics (MD) simulations and quantum chemistry calculations. Our MD simulation results indicate that the ligands form stable complexes with the HN protein through a combination of electrostatic, van der Waals (vdW), and hydrogen bond (H-bond) interactions, which the electrostatic interactions play a more important role in the complexation process. Based on the obtained results from the structural analysis Arg381, Arg291, and Arg49 play a key role in the binding site interactions with the different ligands, in comparison with other residues. There are some candidates such as Neu5Acα2-6Galβ1-4GlcNAcβ, Neu5Acα2-3Galβ1-3GlcNacβ1-3Galβ1-4Glc, and Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4Glc that form more stable complexes with the HN than the α2-3-Sialyllactose confirmed by the calculated Gibbs binding energies (-39.65, -46.93, and -36.49 kcal.mol−1, respectively).To investigate the relationship between the molecular properties of the selected compounds and their affinity to the HN receptor, density functional theory dispersion corrected (DFT-D3) calculations were employed. According to our DFT-D3 results, neutral sialic acid-based compounds have lower reactivity to the mumps virus than the negativity charge structures. Moreover, by increasing the electronic chemical potential (μ) the vdW and H-bond interactions between drugs and the HN protein increase. In other words, by elevating the electron tendency of the selected ligands their affinity to the mumps virus increases. Our quantum chemistry calculations reveal that in addition to the structural features the molecular properties of the drugs can play important roles in their affinity and reactivity against the virus. The results of this study can provide useful details to design new compounds or improve their properties against the mumps virus.

A combined molecular dynamics simulation, DFT calculations, and experimental study of the adsorption of Rhodamine B dye on kaolinite and hydroxyapatite in aqueous solutions

The adsorption efficiency of Rhodamine B (RhB) onto the natural kaolinite and hydroxyapatite (HAP) was investigated. Both adsorbents were characterized using XRD, FTIR, SEM, XRF, and BET surface area analysis. The experimental adsorption tests were optimized by the Box-Behnken design (BBD) which led to conclude the maximal RhB removal obtained by kaolinite (95%) and HAP (84%) using pH=6.5, [RhB]=60 mg/L, and adsorbent mass=1.5 g/L. Molecular dynamics (MD) simulations were finally applied to investigate and predict the mechanisms involved in the adsorption of RhB molecules onto the surface of the kaolinite and HAP. This indicated that the adsorption phenomenon was spontaneous and favorable in the acidic medium with the dominance of Van der Waals interactions. The kinetics investigation showed that the adsorption is well described by the pseudo-second order kinetic (R2 =0.99). The thermodynamics and isotherms studies exhibit that the adsorption phenomenon for both adsorbents is endothermic and significantly fitted with the Freundlich model. The significant RhB adsorption efficiency suggests the potential application of the natural HAP and kaolinite for the removal of the dyes. Moreover, the theoretical study would be of interesting contribution to the advances in the proposed mechanisms of the adsorption process.

Effect of tryptophan mutation on the structure of LOV1 domain of phototropin1 protein of Ostreococcus tauri: A combined molecular dynamics simulation and biophysical approach

BackgroundLight, oxygen and voltage (LOV) proteins detect blue light by formation of a covalent ‘photoadduct’ between the flavin chromophore and the neighboring conserved cysteine residue. LOV proteins devoid of this conserved photoactive cysteine are unable to form this ‘photoadduct’ upon light illumination, but they can still elicit functional response via the formation of neutral flavin radical. Recently, tryptophan residue has been shown to be the primary electron donors to the flavin excited state. MethodsPhotoactive cysteine (Cys42) and tryptophan (Trp68) residues in the LOV1 domain of phototropin1 of Ostreococcus tauri (OtLOV1) was mutated to alanine and threonine respectively. Effect of these mutations have been studied using molecular dynamics simulation and spectroscopic techniques. ResultsMolecular dynamics simulation indicated that W68T did not affect the structure of OtLOV1 protein, but C42A leads to some structural changes. An increase in the fluorescence lifetime and quantum yield values was observed for the Trp68 mutant. ConclusionsAn increase in the fluorescence lifetime and quantum yield of Trp68 mutant compared to the wild type protein suggests that Trp68 residue participates in quenching of the flavin excited state followed by photoexcitation. General significanceEnhanced photo-physical properties of Trp68 OtLOV1 mutant might enable its use for the optogenetic and microscopic applications.

Molecular basis of structural stability of Irisin: A combined molecular dynamics simulation and in vitro studies for Urea-induced denaturation

Irisin is a recently discovered myokine having important role in adipose tissue metabolism, neuronal functioning as well as bone metabolism. In this study, urea-induced denaturation was performed to determine the conformational stability and equilibrium folding intermediate of irisin. Understanding of the folding/unfolding pathway is fundamental to study the structure and stability of proteins. Herein, the urea-induced conformational changes in irisin were monitored employing spectroscopic techniques as well as all-atom molecular dynamics (MD) simulations. It was revealed that process of irisin unfolding is biphasic, i.e., native state (N) ↔ intermediate state (I) ↔ denatured state (D) with I state populated around 2.5 M urea. The stabilized intermediate state at 2.5 M urea was confirmed through binding of the fluorescence probe, 1-anilino-8-naphthalene sulfonate (ANS). Further, 250 ns MD simulation of irisin in urea was carried out to have detailed mechanistic insight. The assessment of structural parameters, free energy landscapes and native contacts indicated the presence of intermediate state during unfolding of irisin, which was characterised as molten globule state. The results of MD simulation showed a strong correlation with the in vitro observations establishing the occurrence of the intermediate population during the unfolding of irisin induced by urea.

Combined molecular dynamics and coordinate driving method for automatically searching complicated reaction pathways.

The combined molecular dynamics and coordinate driving (MD/CD) method is updated and generalized in this work to broaden its applications in automatically searching reaction pathways for complicated reactions. In this updated version, MD simulations are performed with the GFN's family of methods to systematically sample conformers for almost any systems with atomic numbers Z ≤ 86. The improved CD procedure is greatly accelerated by applying a pre-screening stage at the semiempirical GFN2-xTB level. An automatic module based on the Marcus theory and its improved version (the Wolynes theory) is designed to include single electron transfer (SET) processes into reaction pathways. The capabilities of this method are demonstrated by exploring the most possible reaction pathways of three experimentally reported reactions: the organophosphine-catalyzed trans phosphinoboration, the Fe(II) complex-mediated C(sp2)-H borylation reaction, and the SET-triggered deaminative radical cross-coupling reaction. Comprehensive reaction networks are obtained for all three reactions with reasonable computational costs. Detailed mechanisms for these reactions can account for the reported experimental facts.

Exciton diffusion in poly(3-hexylthiophene) by first-principles molecular dynamics.

Poly(3-hexylthiophene) (P3HT) is a polymer used in organic solar cells as a light absorber and an electron donor. Photogenerated excitons diffuse and dissociate into free charge carriers provided they reach the absorber boundaries. The device efficiency is therefore dependent on the exciton diffusion. Although measurements can be performed for example by time-resolved photoluminescence, a quantitative modeling is highly desirable to get an insight into the relationship between the atomic structure at finite temperature and the diffusion coefficient of the exciton. This is the objective of the present work, achieved by resorting to first-principles molecular dynamics in combination with the restricted open-shell approach to model the singlet excited state. The maximally localized Wannier functions and their centers are used to monitor and localize the electron and the hole along the dynamics. The resulting diffusion coefficient is in close agreement with available measurements.

Atomistic simulations for investigation of substrate effects on lipid in-source fragmentation in secondary ion mass spectrometry.

In beam-based ionization methods, the substrate plays an important role on the desorption mechanism of molecules from surfaces. Both the specific orientation that a molecule adopts at a surface and the strength of the molecule-surface interaction can greatly influence desorption processes, which in turn will affect the ion yield and the degree of in-source fragmentation of a molecule. In the beam-based method of secondary ion mass spectrometry (SIMS), in-source fragmentation can be significant and molecule specific due to the hard ionization method of using a primary ion beam for molecule desorption. To investigate the role of the substrate on orientation and in-source fragmentation, we have used atomistic simulations-molecular dynamics in combination with density functional theory calculations-to explore the desorption of a sphingolipid (palmitoylsphingomyelin) from a model surface (gold). We then compare SIMS data from this model system to our modeling findings. Using this approach, we found that the combined adsorption and binding energy of certain bonds associated with the headgroup fragments (C3H8N+, C5H12N+, C5H14NO+, and C5H15PNO4 +) was a good predictor for fragment intensities (as indicated by relative ion yields). This is the first example where atomistic simulations have been applied in beam-based ionization of lipids, and it presents a new approach to study biointerfacial lipid ordering effects on SIMS imaging.