Molecular Dynamics of DNA Translocation by FtsK

The bacterial FtsK motor harvests energy from ATP to translocate double-stranded DNA during cell division. Here, we probe the molecular mechanisms underlying coordinated DNA translocation in FtsK by performing long timescale simulations of its hexameric assembly and individual subunits. From these simulations we predict signaling pathways that connect the ATPase active site to DNA-gripping residues, which allows the motor to coordinate its translocation activity with its ATPase activity. Additionally, we utilize well-tempered metadynamics simulations to compute free-energy landscapes that elucidate the extended-to-compact transition involved in force generation. We show that nucleotide binding promotes a compact conformation of a motor subunit, whereas the apo subunit is flexible. Together, our results support a mechanism whereby each ATP-bound subunit of the motor conforms to the helical pitch of DNA, and ATP hydrolysis/product release causes a subunit to lose grip of DNA. By ordinally engaging and disengaging with DNA, the FtsK motor unidirectionally translocates DNA.

Conical Kresling origami and its applications to curvature and energy programming

Kresling origami has recently been widely used to design mechanical metamaterials, soft robots and smart devices, benefiting from its bistability and compression-twist coupling deformation. However, previous studies mostly focus on the traditional parallelogram Kresling patterns which can only be folded to cylindrical configurations. In this paper, we generalize the Kresling patterns by introducing free-form quadrilateral unit cells, leading to diverse conical folded configurations. The conical Kresling origami is modelled with a truss system, by which the stable states and energy landscapes are derived analytically. We find that the generalization preserves the bistable nature of parallelogram Kresling patterns, while enabling an enlarged design space of geometric parameters for structural and mechanical applications. To demonstrate this, we develop inverse design frameworks to employ conical Kresling origami to approximate arbitrary target surfaces of revolution and achieve prescribed energy landscapes. Various numerical examples obtained from our framework are presented, which agree well with the paper models and the finite-element simulations. We envision that the proposed conical Kresling pattern and inverse design framework can provide a new perspective for applications in deployable structures, shape-morphing devices, multi-modal robots and multistable metamaterials.

Q61 mutant-mediated dynamics changes of the GTP-KRAS complex probed by Gaussian accelerated molecular dynamics and free energy landscapes

Q61 mutants induce structural disorder of the switch domain in KRAS and affect binding of KRAS to effectors.

Nanometer-Scaled Landscape of Polymer:Fullerene Blends Mapped with Visible s-SNOM

Bulk heterojunction is one key concept leading to breakthrough in organic photovoltaics. The active layer is expectantly formed of distinct morphologies that carry out their respective roles in photovoltaic performance. The morphology-performance relationship however remains stymied, because unequivocal morphology at the nanoscale is not available. We used scattering-type scanning near-field optical microscopy operating with a visible light source (visible s-SNOM) to disclose the nanomorphology of P3HT:PCBM and pBCN:PCBM blends. Donor and acceptor domain as well as intermixed phase were identified and their intertwined distributions were mapped. We proposed energy landscapes of the BHJ active layer to shed light on the roles played by these morphologies in charge separation, transport and recombination. This study shows that visible s-SNOM is capable of profiling the morphological backdrop pertaining to the operation of high performance organic solar cells.

Systematic Interrogation of Protein Refolding Under Cellular-Like Conditions

The journey by which proteins navigate their energy landscapes to their native structures is complex, involving (and sometimes requiring) many cellular factors and processes operating in partnership with a given polypeptide chain's intrinsic energy landscape. The cytosolic environment and its complement of chaperones play critical roles in granting proteins safe passage to their native states; however, the complexity of this medium has generally precluded biophysical techniques from interrogating protein folding under cellular-like conditions for single proteins, let alone entire proteomes. Here, we develop a limited-proteolysis mass spectrometry approach paired within an isotope-labeling strategy to globally monitor the structures of refolding E. coli proteins in the cytosolic medium and with the chaperones, GroEL/ES (Hsp60) and DnaK/DnaJ/GrpE (Hsp70/40). GroEL can refold the majority (85%) of the E. coli proteins for which we have data, and is particularly important for restoring acidic proteins and proteins with high molecular weight, trends that come to light because our assay measures the structural outcome of the refolding process itself, rather than indirect measures like binding or aggregation. For the most part, DnaK and GroEL refold a similar set of proteins, supporting the view that despite their vastly different structures, these two chaperones both unfold misfolded states, as one mechanism in common. Finally, we identify a cohort of proteins that are intransigent to being refolded with either chaperone. The data support a model in which chaperone-nonrefolders have evolved to fold efficiently once and only once, co-translationally, and remain kinetically trapped in their native conformations.

Global analysis of crystal energy landscapes: applying the threshold algorithm to molecular crystal structures

We describe the implementation of the Monte Carlo threshold algorithm for molecular crystals as a method to provide an estimate of the energy barriers separating crystal structures. By sampling the local energy minima accessible from multiple starting structures, the simulations yield a global picture of the crystal energy landscapes. This provides valuable information on the depth of the energy minima associated with crystal structures and adds to the information available from crystal structure prediction methods that are used for anticipating polymorphism. We present results from applying the threshold algorithm to four polymorphic organic molecular crystals, examine the influence of applying space group symmetry constraints during the simulations, and discuss the relationship between the structure of the energy landscape and the intermolecular interactions present in the crystals.