Exploring the most stable aptamer/target molecule complex by the stochastic tunnelling-basin hopping-discrete molecular dynamics method

The stochastic tunnelling-basin hopping-discrete molecular dynamics (STUN-BH-DMD) method was applied to the search for the most stable biomolecular complexes in water by using the MARTINI coarse-grained (CG) model. The epithelial cell adhesion molecule (EpCAM, PDB code: 4MZV) was used as an EpCAM adaptor for an EpA (AptEpA) benchmark target molecule. The effects of two adsorption positions on the EpCAM were analysed, and it is found that the AptEpA adsorption configuration located within the EpCAM pocket-like structure is more stable and the energy barrier is lower due to the interaction with water. By the root mean square deviation (RMSD), the configuration of EpCAM in water is more conservative when the AptEpA binds to EpCAM by attaching to the pocket space of the EpCAM dimer. For AptEpA, the root mean square fluctuation (RMSF) analysis result indicates Nucleobase 1 and Nucleobase 2 display higher flexibility during the CGMD simulation. Finally, from the binding energy contour maps and histogram plots of EpCAM and each AptEpA nucleobase, it is clear that the binding energy adsorbed to the pocket-like structure is more continuous than that energy not adsorbed to the pocket-like structure. This study has proposed a new numerical process for applying the STUN-BH-DMD with the CG model, which can reduce computational details and directly find a more stable AptEpA/EpCAM complex in water.

The folding space of protein β2-microglobulin is modulated by a single disulfide bond

Protein beta-2-microglobulin (β2m) is classically considered the causative agent of dialysis related amyloidosis (DRA), a conformational disorder that affects patients undergoing long-term hemodialysis. Together with the wild type form, the ΔN6 structural variant, and the D76N mutant, have been extensively used as model systems of β2m aggregation. In all of them, the native structure is stabilized by a disulfide bridge between the sulphur atoms of the cysteine residues 25 (at B strand) and 80 (at F strand), which has been considered fundamental in β2m fibrillogenesis. Here, we use extensive Discrete Molecular Dynamics simulations of a full atomistic structure-based model to explore the role of this disulfide bridge as a modulator of the folding space of β2m. In particular, by considering different models for the disulfide bridge, we explore the thermodynamics of the folding transition, and the formation of intermediate states that may have the potential to trigger the aggregation cascade. Our results show that the dissulfide bridge affects folding transition and folding thermodynamics of the considered model systems, although to different extents. In particular, when the interaction between the sulphur atoms is stabilized relative to the other intramolecular interactions, or even locked (i.e. permanently established), the WT form populates an intermediate state featuring a well preserved core, and two unstructured termini, which was previously detected only for the D76N mutant. The formation of this intermediate state may have important implications in our understanding of β2m fibrillogenesis.

Adaptive Kinetic Architecture and Collective Behavior: A Dynamic Analysis for Emergency Evacuation

Adaptive kinetic architecture has emerged from a need for innovative designs that adapt to the environment and changing needs of the occupants. Architectural design and modes of egress are critical in an emergency. Flocking describes a certain collective behavior where agents are brought together in groups and move as a cohesive unit from place to place. Collective behavior may be observed in microscopic as well as macroscopic environments. Crowd modeling incorporates the study of human behavior, mathematical modeling, and molecular or fluid dynamics. The simulation of agents and their movement in the built environment is beneficial for design professionals, scientists, and engineers. Human behavior in panic situations is notably similar to fluids and molecules. The objective of this research was to evaluate the movement of agents in buildings using discrete dynamic simulation. We used a novel discrete molecular dynamics technique to simulate the evacuation of agents in panic situations. Various adaptive geometric configurations were analyzed for improved crowd flow. Kinetic walls were modeled in order to evaluate design optimization as it relates to rates of egression. This research proposes the use of kinetic walls to improve safety and efficiency during an emergency evacuation. Adaptive geometric configurations show improvements over the conventional design framework.