Molecular dynamics simulations were performed of the adsorption of methylene blue (MB) on model beidellite, montmorillonite, and muscovite mica surfaces, using a previously determined empirical force field developed for dioctahedral clays. The simulations show that the adsorption of MB on mineral surfaces can result in a variety of configurations, including single and double layers of MB parallel to the basal surface, and irregular clusters. The d(001) values of ~12.3 and ~15.7 Å are assigned to dry phases with parallel single and double layers of MB, respectively, in agreement with X-ray studies. At intermediate MB loadings, stacks inclined to basal surfaces are formed. The stacks of MB ions inclined by 65–70° relative to the (001) plane of muscovite are not found on dry surfaces, in contrast to previous studies. Configurations similar to those proposed by others form spontaneously in the presence of H2O, but the ions in the model systems are not quite as ordered and not ordered in exactly the same way as the ones previously described, and they display a mobility that is not compatible with strict atomic order. The formation of a triple layer of H2O interspersed with ions may occur in the interlayer. Overall, the results of the simulations confirm that the MB-ion method must be used with great caution in surface-area determinations, because of the multiplicity of possible configurations. At the same time, the ability for adsorption to occur as either single or multiple MB layers is useful to determine cation-exchange capacity over a wide range of surface-charge densities.

This work presents Atomistic Topology Operations in MATLAB (atom), an open source library of modular MATLAB routines which comprise a general and flexible framework for manipulation of atomistic systems. The purpose of the atom library is simply to facilitate common operations performed for construction, manipulation, or structural analysis. Due to the data structure used, atoms and molecules can be operated upon based on different chemical names or attributes, such as atom- or molecule-ID, name, residue name, charge, positions, etc. Furthermore, the Bond Valence Method and a neighbor-distance analysis can be performed to assign many chemical properties of inorganic molecules. Apart from reading and writing common coordinate files (.pdb, .xyz, .gro, .cif) and trajectories (.dcd, .trr, .xtc; binary formats are parsed via third-party packages), the atom library can also be used to generate topology files with bonding and angle information taking the periodic boundary conditions into account, and supports basic Gromacs, NAMD, LAMMPS, and RASPA2 topology file formats. Focusing on clay-mineral systems, the library supports CLAYFF (Cygan, 2004) but can also generate topology files for the INTERFACE forcefield (Heinz, 2005, 2013) for Gromacs and NAMD.

Selective DNA binding by transcription factors (TFs) is crucial for the correct regulation of DNA transcription. In healthy cells, promoters of active genes are hypomethylated. A single CpG methylation within a TF response element (RE) may change the binding preferences of the protein, thus causing the dysregulation of transcription programs. Here, we investigate a molecular mechanism driving the downregulation of the NDUFA13 gene, due to hypermethylation, which is associated with multiple cancers. Using bioinformatic analyses of breast cancer cell line MCF7, we identify a hypermethylated region containing the binding sites of two TFs dimers, CEBPB and E2F1-DP1, located 130 b.p. from the gene transcription start site. All-atom extended MD simulations of wild type and methylated DNA alone and in complex with either one or both TFs dimers provide mechanistic insights into the cooperative asymmetric binding order of the two dimers; the CEBPB binding should occur first to facilitate the E2F1-DP1–DNA association. The CpG methylation within the E2F1-DP1 RE and the linker decrease the cooperativity effects and renders the E2F1-DP1 binding site less recognizable by the TF dimer. Taken together, the identified CpG methylation site may contribute to the downregulation of the NDUFA13 gene.

Changing torsional restraints on DNA is essential for the regulation of transcription. Torsional stress, introduced by RNA polymerase, can propagate along chromatin facilitating topological transitions and modulating the specific binding of transcription factors (TFs) to DNA. Despite the importance, the mechanistic details on how torsional stress impacts the TFs-DNA complexation remain scarce. Herein, we address the impact of torsional stress on DNA complexation with homologous human basic helix–loop–helix (BHLH) hetero- and homodimers: MycMax, MadMax and MaxMax. The three TF dimers exhibit specificity towards the same DNA consensus sequence, the E-box response element, while regulating different transcriptional pathways. Using microseconds-long atomistic molecular dynamics simulations together with the torsional restraint that controls DNA total helical twist, we gradually over- and underwind naked and complexed DNA to a maximum of ± 5°/bp step. We observe that the binding of the BHLH dimers results in a similar increase in DNA torsional rigidity. However, under torsional stress the BHLH dimers induce distinct DNA deformations, characterised by changes in DNA grooves geometry and a significant asymmetric DNA bending. Supported by bioinformatics analyses, our data suggest that torsional stress may contribute to the execution of differential transcriptional programs of the homologous TFs by modulating their collaborative interactions.

RNA molecules play many functional and regulatory roles in cells, and hence, have gained considerable traction in recent times as therapeutic interventions. Within drug discovery, structure-based approaches have successfully identified potent and selective small-molecule modulators of pharmaceutically relevant protein targets. Here, we embrace the perspective of computational chemists who use these traditional approaches, and we discuss the challenges of extending these methods to target RNA molecules. In particular, we focus on recognition between RNA and small-molecule binders, on selectivity, and on the expected properties of RNA ligands.

This study investigated influences of vacancy defects on buckling behaviors of open-tip carbon nanocones (CNCs) by molecular dynamics simulations. Effects of vacancy location and temperature on the buckling behaviors were examined in the study. Some interesting findings were attained from the investigations. It was noticed that the CNC with an upper vacancy has comparable degradation in the critical strain and in the critical load with the CNC with a middle vacancy, whereas the CNC with a lower vacancy has lower degradation in the antibuckling ability than the above two CNCs. The antibuckling ability of the CNCs reduces with the growth of the temperature. This temperature effect is more apparent in the perfect CNC than in the vacancy-defect CNCs. It was also observed that the degradation in the antibuckling ability is obvious at a lower temperature, but it decreases as the temperature grows. Besides, all the CNCs (including the perfect and the vacancy-defect CNCs) exhibited a shrinking/swelling buckling mode shape at the studied temperatures. Existence of the vacancies did not alter the buckling mode shape of the CNCs.

When liquids solidify, the interface between a crystal and its melt often forms branching structures (dendrites), just as frost spreads across a window. The development of a quantitative understanding of dendritic evolution continues to present a major theoretical and experimental challenge within the metallurgical community. This article looks at key parameters that describe the interface—excess free energy and mobility—and discusses how these important properties relate to our understanding of crystal growth and other interfacial phenomena such as wetting and spreading of droplets and nucleation of the solid phase from the melt. In particular, two new simulation methods have emerged for computing the interfacial free energy and its anisotropy:the cleaving technique and the capillary fluctuation method. These are presented, along with methods for extracting the kinetic coefficient and a comparison of the results to several theories of crystal growth rates.

A method is presented that allows the calculation of the lifetimes of tryptophan residues on the basis of spectral and structural data. It is applied to two different proteins. The calcium binding protein from the sarcoplasm of the muscles of the sand worm Nereis diversicolor (NSCP) changes its conformation upon binding of Ca2+ or Mg2+. NSCP contains three tryptophan residues at position 4, 57, and 170, respectively. The fluorescence lifetimes of W57 are investigated in a mutant in which W4 and W170 have been replaced. The time resolved fluorescence properties of W57 are linked to its different microconformations, which were determined by a molecular dynamics simulation map. Together with the determination of the radiative rate constant from the wavelength of maximum intensity of the decay associated spectra, it was possible to determine an exponential relation between the nonradiative rate constant and the distance between the indole CE3 atom and the carbonyl carbon of the peptide bond reflecting a mechanism of electron transfer as the main determinant of the value for the nonradiative rate constant. This result allows the calculation of the fluorescence lifetimes from the protein structure and the spectra. This method was further tested for the tryptophan of Ha-ras p21 (W32) and for W43 of the Tet repressor, which resulted in acceptable values for the predicted lifetimes.

Molecular dynamics calculations provide a method by which the dynamic properties of molecules can be explored over timescales and at a level of detail that cannot be obtained experimentally from NMR or X-ray analyses. Recent work (Philippopoulos M, Mandel AM, Palmer AG III, Lim C, 1997, Proteins 28:481–493) has indicated that the accuracy of these simulations is high, as measured by the correspondence of parameters extracted from these calculations to those determined through experimental means. Here, we investigate the dynamic behavior of the Src homology 3 (SH3) domain of hematopoietic cell kinase (Hck) via 15N backbone relaxation NMR studies and a set of four independent 4 ns solvated molecular dynamics calculations. We also find that molecular dynamics simulations accurately reproduce fast motion dynamics as estimated from generalized order parameter (S2) analysis for regions of the protein that have experimentally well-defined coordinates (i.e., stable secondary structural elements). However, for regions where the coordinates are not well defined, as indicated by high local root-mean-square deviations among NMR-determined structural family members or high B-factors/low electron density in X-ray crystallography determined structures, the parameters calculated from a short to moderate length (less than 5–10 ns) molecular dynamics trajectory are dependent on the particular coordinates chosen as a starting point for the simulation.

The U1A protein binds to a hairpin RNA and an internal-loop RNA with picomolar affinities. To probe the molecular basis of U1A binding, we performed state-of-the-art nanosecond molecular dynamics simulations on both complexes. The good agreement with experimental structures supports the protocols used in the simulations. We compare the dynamics, hydrogen-bonding occupancies, and interfacial flexibility of both complexes and also describe a rigid-body motion in the U1A–internal loop complex that is not observed in the U1A–hairpin simulation. We relate these observations to experimental mutational studies and highlight their significance in U1A binding affinity and specificity.