Non-Stokesian dynamics of magnetic helical nanoswimmers under confinement.

Electromagnetically propelled helical nanoswimmers offer great potential for nanorobotic applications. Here, the effect of confinement on their propulsion is characterized using lattice-Boltzmann simulations. Two principal mechanisms give rise to their forward motion under confinement: (i) pure swimming and (ii) the thrust created by the differential pressure due to confinement. Under strong confinement, they face greater rotational drag but display a faster propulsion for fixed driving frequency in agreement with experimental findings. This is due to the increased differential pressure created by the boundary walls when they are sufficiently close to each other and the particle. We have proposed two analytical relations (i) for predicting the swimming speed of an unconfined particle as a function of its angular speed and geometrical properties, and (ii) an empirical expression to accurately predict the propulsion speed of a confined swimmer as a function of the degree of confinement and its unconfined swimming speed. At low driving frequencies and degrees of confinement, the systems retain the expected linear behavior consistent with the predictions of the Stokes equation. However, as the driving frequency and/or the degree of confinement increase, their impact on propulsion leads to increasing deviations from the Stokesian regime and emergence of nonlinear behavior.

Chemoselective Staudinger Reactivity of Bis(azido)phosphines Supported with a π-Donating Imidazolin-2-iminato Ligand.

Synthesis and characterization of new P(III) and P(V) bis(azido)phosphines/phosphoranes supported by an N,N'-bis(2,6-diisopropylphenyl) imidazolin-2-iminato (IPrN) ligand and their reactivity with various secondary and tertiary phosphines result in the formation of chiral and/or asymmetric mono(phosphinimino)azidophosphines via the Staudinger reaction. The reaction of IPrNP(N3)2 (2) or IPrNP(S)(N3)2 (4S) with an excess of tertiary phosphine resulted in the chemoselective formation of IPrNP(N3)(NPMe3) (7) or IPrNP(S)N3(NPR3) (5R), respectively. The chemoselective Staudinger reactivity was also observed in reactions using a secondary phosphine (HPCy2) to produce IPrNP(S)N3[NP(H)Cy2] (6a), which exists in equilibrium with a tautomeric IPrNP(S)N3[N(H)PCy2] form (6b), as confirmed by 31P-31P nuclear Overhauser effect spectroscopy (NOESY). Density functional theory (DFT) calculations point to a combination of energetically unfavorable lowest unoccupied molecular orbitals (LUMOs) and the accumulation of increasing negative charge at the terminal azido-nitrogen upon a single azide-to-phosphinimine conversion that gave rise to the observed chemoselectivity.

A Molecular Dynamics Simulation Study of the Effects of ßGln114 Mutation on the Dynamic Behavior of the Catalytic Site of the Tryptophan Synthase.

L-tryptophan (l-Trp), a vital amino acid for the survival of various organisms, is synthesized by the enzyme tryptophan synthase (TS) in organisms such as eubacteria, archaebacteria, protista, fungi, and plantae. TS, a pyridoxal 5'-phosphate (PLP)-dependent enzyme, comprises α and ß subunits that typically form an α2ß2 tetramer. The enzyme's activity is regulated by the conformational switching of its α and ß subunits between the open (T state) and closed (R state) conformations. Many microorganisms rely on TS for growth and replication, making the enzyme and the l-Trp biosynthetic pathway potential drug targets. For instance, Mycobacterium tuberculosis, Chlamydiae bacteria, Streptococcus pneumoniae, Francisella tularensis, Salmonella bacteria, and Cryptosporidium parasitic protozoa depend on l-Trp synthesis. Antibiotic-resistant salmonella strains have emerged, underscoring the need for novel drugs targeting the l-Trp biosynthetic pathway, especially for salmonella-related infections. A single amino acid mutation can significantly impact enzyme function, affecting stability, conformational dynamics, and active or allosteric sites. These changes influence interactions, catalytic activity, and protein-ligand/protein-protein interactions. This study focuses on the impact of mutating the ßGln114 residue on the catalytic and allosteric sites of TS. Extensive molecular dynamics simulations were conducted on E(PLP), E(AEX1), E(A-A), and E(C3) forms of TS using the WT, ßQ114A, and ßQ114N versions. The results show that both the ßQ114A and ßQ114N mutations increase protein backbone root mean square deviation fluctuations, destabilizing all TS forms. Conformational and hydrogen bond analyses suggest the significance of ßGln114 drifting away from cofactor/intermediates and forming hydrogen bonds with water molecules necessary for l-Trp biosynthesis. The ßQ114A mutation creates a gap between ßAla114 and cofactor/intermediates, hindering hydrogen bond formation due to short side chains and disrupting ß-sites. Conversely, the ßQ114N mutation positions ßAsn114 closer to cofactor/intermediates, forming hydrogen bonds with O3 of cofactors/intermediates and nearby water molecules, potentially disrupting the l-Trp biosynthetic mechanism.

Effect of substrate heterogeneity and topology on epithelial tissue growth dynamics.

Tissue growth kinetics and interface dynamics depend on the properties of the tissue environment and cell-cell interactions. In cellular environments, substrate heterogeneity and geometry arise from a variety factors, such as the structure of the extracellular matrix and nutrient concentration. We used the CellSim3D model, a kinetic cell division simulator, to investigate the growth kinetics and interface roughness dynamics of epithelial tissue growth on heterogeneous substrates with varying topologies. The results show that the presence of quenched disorder has a clear effect on the colony morphology and the roughness scaling of the interface in the moving interface regime. In a medium with quenched disorder, the tissue interface has a smaller interface roughness exponent, α, and a larger growth exponent, ß. The scaling exponents also depend on the topology of the substrate and cannot be categorized by well-known universality classes.

Accurately Predicting Protein pKa Values Using Nonequilibrium Alchemy.

The stability, solubility, and function of a protein depend on both its net charge and the protonation states of its individual residues. pKa is a measure of the tendency for a given residue to (de)protonate at a specific pH. Although pKa values can be resolved experimentally, theory and computation provide a compelling alternative. To this end, we assess the applicability of a nonequilibrium (NEQ) alchemical free energy method to the problem of pKa prediction. On a data set of 144 residues that span 13 proteins, we report an average unsigned error of 0.77 ± 0.09, 0.69 ± 0.09, and 0.52 ± 0.04 pK for aspartate, glutamate, and lysine, respectively. This is comparable to current state-of-the-art predictors and the accuracy recently reached using free energy perturbation methods (e.g., FEP+). Moreover, we demonstrate that our open-source, pmx-based approach can accurately resolve the pKa values of coupled residues and observe a substantial performance disparity associated with the lysine partial charges in Amber14SB/Amber99SB*-ILDN, for which an underused fix already exists.

Effect of oxidation on POPC lipid bilayers: anionic carboxyl group plays a major role.

Phospholipids with unsaturated acyl chains are major targets of reactive oxygen species leading to formation of oxidized lipids. Oxidized phospholipids have a pronounced role in cell membrane damage. We investigated the effect of oxidation on physiological properties of phospholipid bilayers using atomistic molecular dynamics simulations. We studied phospholipid bilayer systems of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and its two stable oxidized products, 1-palmitoyl-2-(9'-oxo-nonanoyl)-sn-glycero-3-phosphocholine (PoxnoPC) and 1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine (PazePC). Structural properties of the POPC lipid bilayer upon the addition of PoxnoPC or PazePC with concentration ranging from 10% to 30% were described. The key finding is that PazePC lipids bend their polar tails toward the bilayer-water interface whereas PoxnoPC lipids orient their tail toward the bilayer interior. The bilayer thickness decreases such that the thickness reduction in bilayers containing PazePC is stronger than in bilayers containing PoxnoPC. The average area per lipid decreases with a stronger effect in bilayers containing PoxnoPC. The addition of PoxnoPC makes both POPC acyl chains slightly more ordered whereas the addition of PazePC reduces the order in the two POPC acyl chains. These structural changes lead to an enhancement in the permeabilities of the bilayers containing these two oxidized products depending on the type, and the amount of oxidation. This enhancement can be achieved with a lower concentration of PazePC (10% or 15%), whereas a higher concentration of PoxnoPC (20%) is required to achieve an apparent enhancement in permeability. While the permeability of bilayers containing PazePC is higher than bilayers containing PoxnoPC in the 10-20% concentration range, by increasing the concentration of the oxidized products to higher than 20%, permeability of the bilayers containing PazePC is reduced such that it is slightly smaller than those containing PoxnoPC.

Identification of Catechins' Binding Sites in Monomeric Aß42 through Ensemble Docking and MD Simulations.

The assembly of the amyloid-ß peptide (Aß) into toxic oligomers and fibrils is associated with Alzheimer's disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aß monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aß, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline-in the framework of the ensemble docking strategy-to identify catechins' binding sites in monomeric Aß42. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aß42. Additionally, it has been found that all the studied ligands, especially EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of Aß. Our findings are evaluated and confirmed with multi-microsecond MD simulations. Finally, it is suggested that our proposed pipeline, with low computational cost in comparison with MD simulations, is a suitable approach for the virtual screening of ligand libraries against Aß.

Elucidating lipid conformations in the ripple phase: Machine learning reveals four lipid populations.

A new mixed radial-angular, three-particle correlation function method in combination with unsupervised machine learning was applied to examine the emergence of the ripple phase in dipalmitoylphosphatidylcholine (DPPC) lipid bilayers using data from atomistic molecular dynamics simulations of system sizes ranging from 128 to 4096 lipids. Based on the acyl tail conformations, the analysis revealed the presence of four distinct conformational populations of lipids in the ripple phases of the DPPC lipid bilayers. The expected gel-like (ordered; Lo) and fluid-like (disordered; Ld) lipids are found along with their splayed tail equivalents (Lo,s and Ld,s). These lipids differ, based on their gauche distribution and tail packing. The disordered (Ld) and disordered-splayed (Ld,s) lipids spatially cluster in the ripple in the groove side, that is, in an asymmetric manner across the bilayer leaflets. The ripple phase does not contain large numbers of Ld lipids; instead they only exist on the interface of the groove side of the undulation. The bulk of the groove side is a complex coexistence of Lo,Lo,s, and Ld,s lipids. The convex side of the undulation contains predominantly Lo lipids. Thus, the structure of the ripple phase is neither a simple coexistence of ordered and disordered lipids nor a coexistence of ordered interdigitating gel-like (Lo) and ordered-splayed (Lo,s) lipids, but instead a coexistence of an ordered phase and a complex mixed phase. Principal component analysis further confirmed the existence of the four lipid groups.

Structural Investigation of DHICA Eumelanin Using Density Functional Theory and Classical Molecular Dynamics Simulations.

Eumelanin is an important pigment, for example, in skin, hair, eyes, and the inner ear. It is a highly heterogeneous polymer with 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and 5,6-dihydroxyindole (DHI) building blocks, of which DHICA is reported as the more abundant in natural eumelanin. The DHICA-eumelanin protomolecule consists of three building blocks, indole-2-carboxylic acid-5,6-quinone (ICAQ), DHICA and pyrrole-2,3,5-tricarboxylic acid (PTCA). Here, we focus on the self-assembly of DHICA-eumelanin using multi-microsecond molecular dynamics (MD) simulations at various concentrations in aqueous solutions. The molecule was first parameterized using density functional theory (DFT) calculations. Three types of systems were studied: (1) uncharged DHICA-eumelanin, (2) charged DHICA-eumelanin corresponding to physiological pH, and (3) a binary mixture of both of the above protomolecules. In the case of uncharged DHICA-eumelanin, spontaneous aggregation occurred and water molecules were present inside the aggregates. In the systems corresponding to physiological pH, all the carboxyl groups are negatively charged and the DHICA-eumelanin model has a net charge of -4. The effect of K+ ions as counterions was investigated. The results show high probability of binding to the deprotonated oxygens of the carboxylate anions in the PTCA moiety. Furthermore, the K+ counterions increased the solubility of DHICA-eumelanin in its charged form. A possible explanation is that the charged protomolecules favor binding to the K+ ions rather than aggregating and binding to other protomolecules. The binary mixtures show aggregation of uncharged DHICA-eumelanins; unlike the charged systems with no aggregation, a few charged DHICA-eumelanins are present on the surface of the uncharged aggregation, binding to the K+ ions.

Temperature-resilient anapole modes associated with TE polarization in semiconductor nanowires.

Polarization-dependent scattering anisotropy of cylindrical nanowires has numerous potential applications in, for example, nanoantennas, photothermal therapy, thermophotovoltaics, catalysis, sensing, optical filters and switches. In all these applications, temperature-dependent material properties play an important role and often adversely impact performance depending on the dominance of either radiative or dissipative damping. Here, we employ numerical modeling based on Mie scattering theory to investigate and compare the temperature and polarization-dependent optical anisotropy of metallic (gold, Au) nanowires with indirect (silicon, Si) and direct (gallium arsenide, GaAs) bandgap semiconducting nanowires. Results indicate that plasmonic scattering resonances in semiconductors, within the absorption band, deteriorate with an increase in temperature whereas those occurring away from the absorption band strengthen as a result of the increase in phononic contribution. Indirect-bandgap thin ([Formula: see text]) Si nanowires present low absorption efficiencies for both the transverse electric (TE, [Formula: see text]) and magnetic (TM, [Formula: see text]) modes, and high scattering efficiencies for the TM mode at shorter wavelengths making them suitable as highly efficient scatterers. Temperature-resilient higher-order anapole modes with their characteristic high absorption and low scattering efficiencies are also observed in the semiconductor nanowires ([Formula: see text] nm) for the TE polarization. Herein, the GaAs nanowires present [Formula: see text] times greater absorption efficiencies compared to the Si nanowires making them especially suitable for temperature-resilient applications such as scanning near-field optical microscopy (SNOM), localized heating, non-invasive sensing or detection that require strong localization of energy in the near field.

AlphaFold2: A Role for Disordered Protein/Region Prediction?

The development of AlphaFold2 marked a paradigm-shift in the structural biology community. Herein, we assess the ability of AlphaFold2 to predict disordered regions against traditional sequence-based disorder predictors. We find that AlphaFold2 performs well at discriminating disordered regions, but also note that the disorder predictor one constructs from an AlphaFold2 structure determines accuracy. In particular, a naïve, but non-trivial assumption that residues assigned to helices, strands, and H-bond stabilized turns are likely ordered and all other residues are disordered results in a dramatic overestimation in disorder; conversely, the predicted local distance difference test (pLDDT) provides an excellent measure of residue-wise disorder. Furthermore, by employing molecular dynamics (MD) simulations, we note an interesting relationship between the pLDDT and secondary structure, that may explain our observations and suggests a broader application of the pLDDT for characterizing the local dynamics of intrinsically disordered proteins and regions (IDPs/IDRs).

Fullerenes' Interactions with Plasma Membranes: Insight from the MD Simulations.

Understanding the interactions between carbon nanoparticles (CNPs) and biological membranes is critically important for applications of CNPs in biomedicine and toxicology. Due to the complexity and diversity of the systems, most molecular simulation studies have focused on the interactions of CNPs and single component bilayers. In this work, we performed coarse-grained molecular dynamic (CGMD) simulations to investigate the behaviors of fullerenes in the presence of multiple lipid components in the plasma membranes with varying fullerene concentrations. Our results reveal that fullerenes can spontaneously penetrate the plasma membrane. Interestingly, fullerenes prefer to locate themselves in the region of the highly unsaturated lipids that are enriched in the inner leaflet of the plasma membrane. This causes fullerene aggregation even at low concentrations. When increasing fullerene concentrations, the fullerene clusters grow, and budding may emerge at the inner leaflet of the plasma membrane. Our findings suggest by tuning the lipid composition, fullerenes can be loaded deeply inside the plasma membrane, which can be useful for designing drug carrier liposomes. Moreover, the mechanisms of how fullerenes perturb multicomponent cell membranes and how they directly enter the cell are proposed. These insights can help to determine fullerene toxicity in living cells.

Collective interactions among organometallics are exotic bonds hidden on lab shelves.

Recent discovery of an unusual bond between Na and B in NaBH3- motivated us to look for potentially similar bonds, which remained unnoticed among systems isoelectronic with NaBH3-. Here, we report a novel family of collective interactions and a measure called exchange-correlation interaction collectivity index (ICIXC; [Formula: see text]) to characterize the extent of collective versus pairwise bonding. Unlike conventional bonds in which ICIXC remains close to one, in collective interactions ICIXC may approach zero. We show that collective interactions are commonplace among widely used organometallics, as well as among boron and aluminum complexes with the general formula [Ma+AR3]b- (A: C, B or Al). In these species, the metal atom interacts more efficiently with the substituents (R) on the central atoms than the central atoms (A) upon forming efficient collective interactions. Furthermore, collective interactions were also found among fluorine atoms of XFn systems (X: B or C). Some of organolithium and organomagnesium species have the lowest ICIXC among the more than 100 studied systems revealing the fact that collective interactions are rather a rule than an exception among organometallic species.

Osmotic Method for Calculating Surface Pressure of Monolayers in Molecular Dynamics Simulations.

Surface pressure is a fundamental thermodynamic property related to the activity of molecules at interfaces. In molecular simulations, it is typically calculated from its definition: the difference between the surface tension of the air-water and air-surfactant interfaces. In this Letter, we show how to connect the surface pressure with a two-dimensional osmotic pressure and how to take advantage of this analogy to obtain a practical method of calculating surface pressure-area isotherms in molecular simulation. As a proof-of-concept, compression curves of zwitterionic and ionic surfactant monolayers were obtained using the osmotic approach and the curves were compared with the ones from the traditional pressure tensor-based scheme. The results shown an excellent agreement between both alternatives. Advantageously, the osmotic approach is simple to use and allows to obtain the surface pressure-area isotherm on the fly with a single simulation using equilibration stages.

Free Energy and Stacking of Eumelanin Nanoaggregates.

Eumelanin, a member of the melanin family, is a black-brown insoluble pigment. It possesses a broad range of properties such as antioxidation, free radical scavenging, photoprotection, and charge carrier transportation. Surprisingly, the exact molecular structure of eumelanin remains undefined. It is, however, generally considered to consist of two main building blocks, 5,6-dihydroxyindole (DHI) and 5,6- dihydroxyindole carboxylic acid (DHICA). We focus on DHI and report, for the first time, a computational investigation of the structural properties of DHI-eumelanin aggregates in aqueous solutions. First, multimicrosecond molecular dynamics (MD) simulations at different concentrations were performed to investigate the aggregation and ordering of tetrameric DHI-eumelanin protomolecules. This was followed by umbrella sampling (US) and density functional theory (DFT) calculations to study the physical mechanisms of stacking. Aggregation occurs through formation of nanoscale stacks and was observed in all systems. Further analyses showed that aggregation and coarsening of the domains is due to a decrease in hydrogen bonds between the eumelanins and water; while domains exist, there is no long-range order. The results show noncovalent stacks with the interlayer distance between eumelanin protomolecules being less than 3.5 Å. This is in good agreement with transmission electron microscopy data. Both free energy calculations and DFT revealed strong stacking interactions. The electrostatic potential map provides an explanation and a rationale for the slightly sheared relative orientations and, consequently, for the curved shapes of the nanoscale domains.

Multiscale Computational Study of the Conformation of the Full-Length Intrinsically Disordered Protein MeCP2.

The malfunction of the methyl-CpG binding protein 2 (MeCP2) is associated with the Rett syndrome, one of the most common causes of cognitive impairment in females. MeCP2 is an intrinsically disordered protein (IDP), making its experimental characterization a challenge. There is currently no structure available for the full-length MeCP2 in any of the databases, and only the structure of its MBD domain has been solved. We used this structure to build a full-length model of MeCP2 by completing the rest of the protein via ab initio modeling. Using a combination of all-atom and coarse-grained simulations, we characterized its structure and dynamics as well as the conformational space sampled by the ID and transcriptional repression domain (TRD) domains in the absence of the rest of the protein. The present work is the first computational study of the full-length protein. Two main conformations were sampled in the coarse-grained simulations: a globular structure similar to the one observed in the all-atom force field and a two-globule conformation. Our all-atom model is in good agreement with the available experimental data, predicting amino acid W104 to be buried, amino acids R111 and R133 to be solvent-accessible, and having a 4.1% α-helix content, compared to the 4% found experimentally. Finally, we compared the model predicted by AlphaFold to our Modeller model. The model was not stable in water and underwent further folding. Together, these simulations provide a detailed (if perhaps incomplete) conformational ensemble of the full-length MeCP2, which is compatible with experimental data and can be the basis of further studies, e.g., on mutants of the protein or its interactions with its biological partners.

Changes in the Local Conformational States Caused by Simple Na+ and K+ Ions in Polyelectrolyte Simulations: Comparison of Seven Force Fields with and without NBFIX and ECC Corrections.

Electrostatic interactions have a determining role in the conformational and dynamic behavior of polyelectrolyte molecules. In this study, anionic polyelectrolyte molecules, poly(glutamic acid) (PGA) and poly(aspartic acid) (PASA), in a water solution with the most commonly used K+ or Na+ counterions, were investigated using atomistic molecular dynamics (MD) simulations. We performed a comparison of seven popular force fields, namely AMBER99SB-ILDN, AMBER14SB, AMBER-FB15, CHARMM22*, CHARMM27, CHARMM36m and OPLS-AA/L, both with their native parameters and using two common corrections for overbinding of ions, the non-bonded fix (NBFIX), and electronic continuum corrections (ECC). These corrections were originally introduced to correct for the often-reported problem concerning the overbinding of ions to the charged groups of polyelectrolytes. In this work, a comparison of the simulation results with existing experimental data revealed several differences between the investigated force fields. The data from these simulations and comparisons with previous experimental data were then used to determine the limitations and strengths of these force fields in the context of the structural and dynamic properties of anionic polyamino acids. Physical properties, such as molecular sizes, local structure, and dynamics, were studied using two types of common counterions, namely potassium and sodium. The results show that, in some cases, both the macroion size and dynamics depend strongly on the models (parameters) for the counterions due to strong overbinding of the ions and charged side chain groups. The local structures and dynamics are more sensitive to dihedral angle parameterization, resulting in a preference for defined monomer conformations and the type of correction used. We also provide recommendations based on the results.

Computer Simulations of Deep Eutectic Solvents: Challenges, Solutions, and Perspectives.

Deep eutectic solvents (DESs) are one of the most rapidly evolving types of solvents, appearing in a broad range of applications, such as nanotechnology, electrochemistry, biomass transformation, pharmaceuticals, membrane technology, biocomposite development, modern 3D-printing, and many others. The range of their applicability continues to expand, which demands the development of new DESs with improved properties. To do so requires an understanding of the fundamental relationship between the structure and properties of DESs. Computer simulation and machine learning techniques provide a fruitful approach as they can predict and reveal physical mechanisms and readily be linked to experiments. This review is devoted to the computational research of DESs and describes technical features of DES simulations and the corresponding perspectives on various DES applications. The aim is to demonstrate the current frontiers of computational research of DESs and discuss future perspectives.

Highly Similar Sequence and Structure Yet Different Biophysical Behavior: A Computational Study of Two Triosephosphate Isomerases.

Homodimeric triosephosphate isomerases (TIMs) from Trypanosoma cruzi (TcTIM) and Trypanosoma brucei (TbTIM) have markedly similar amino-acid sequences and three-dimensional structures. However, several of their biophysical parameters, such as their susceptibility to sulfhydryl agents and their reactivation speed after being denatured, have significant differences. The causes of these differences were explored with microsecond-scale molecular dynamics (MD) simulations of three different TIM proteins: TcTIM, TbTIM, and a chimeric protein, Mut1. We examined their electrostatic interactions and explored the impact of simulation length on them. The same salt bridge between catalytic residues Lys 14 and Glu 98 was observed in all three proteins, but key differences were found in other interactions that the catalytic amino acids form. In particular, a cation-π interaction between catalytic amino acids Lys 14 and His 96 and both a salt bridge and a hydrogen bond between catalytic Glu 168 and residue Arg 100 were only observed in TcTIM. Furthermore, although TcTIM forms less hydrogen bonds than TbTIM and Mut1, its hydrogen bond network spans almost the entire protein, connecting the residues in both monomers. This work provides new insight into the mechanisms that give rise to the different behavior of these proteins. The results also show the importance of long simulations.