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1. Electrical unfolding of cytochrome c during translocation through a nanopore constriction

   https://doi.org/10.1073/pnas.2016262118  

   Tripathi, Prabhat; Benabbas, Abdelkrim; Mehrafrooz, Behzad; Yamazaki, Hirohito; Aksimentiev, Aleksei; Champion, Paul M.; Wanunu, Meni (April 2021, Proceedings of the National Academy of Sciences)

   null (Ed.)

   Many small proteins move across cellular compartments through narrow pores. In order to thread a protein through a constriction, free energy must be overcome to either deform or completely unfold the protein. In principle, the diameter of the pore, along with the effective driving force for unfolding the protein, as well as its barrier to translocation, should be critical factors that govern whether the process proceeds via squeezing, unfolding/threading, or both. To probe this for a well-established protein system, we studied the electric-field–driven translocation behavior of cytochrome c (cyt c ) through ultrathin silicon nitride (SiN x ) solid-state nanopores of diameters ranging from 1.5 to 5.5 nm. For a 2.5-nm-diameter pore, we find that, in a threshold electric-field regime of ∼30 to 100 MV/m, cyt c is able to squeeze through the pore. As electric fields inside the pore are increased, the unfolded state of cyt c is thermodynamically stabilized, facilitating its translocation. In contrast, for 1.5- and 2.0-nm-diameter pores, translocation occurs only by threading of the fully unfolded protein after it transitions through a higher energy unfolding intermediate state at the mouth of the pore. The relative energies between the metastable, intermediate, and unfolded protein states are extracted using a simple thermodynamic model that is dictated by the relatively slow (∼ms) protein translocation times for passing through the nanopore. These experiments map the various modes of protein translocation through a constriction, which opens avenues for exploring protein folding structures, internal contacts, and electric-field–induced deformability. 

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2. Friends in need: How chaperonins recognize and remodel proteins that require folding assistance

   https://doi.org/10.3389/fmolb.2022.1071168  

   Stan, George; Lorimer, George H.; Thirumalai, D. (November 2022, Frontiers in Molecular Biosciences)

   Chaperonins are biological nanomachines that help newly translated proteins to fold by rescuing them from kinetically trapped misfolded states. Protein folding assistance by the chaperonin machinery is obligatory in vivo for a subset of proteins in the bacterial proteome. Chaperonins are large oligomeric complexes, with unusual seven fold symmetry (group I) or eight/nine fold symmetry (group II), that form double-ring constructs, enclosing a central cavity that serves as the folding chamber. Dramatic large-scale conformational changes, that take place during ATP-driven cycles, allow chaperonins to bind misfolded proteins, encapsulate them into the expanded cavity and release them back into the cellular environment, regardless of whether they are folded or not. The theory associated with the iterative annealing mechanism, which incorporated the conformational free energy landscape description of protein folding, quantitatively explains most, if not all, the available data. Misfolded conformations are associated with low energy minima in a rugged energy landscape. Random disruptions of these low energy conformations result in higher free energy, less folded, conformations that can stochastically partition into the native state. Two distinct mechanisms of annealing action have been described. Group I chaperonins (GroEL homologues in eubacteria and endosymbiotic organelles), recognize a large number of misfolded proteins non-specifically and operate through highly coordinated cooperative motions. By contrast, the less well understood group II chaperonins (CCT in Eukarya and thermosome/TF55 in Archaea), assist a selected set of substrate proteins. Sequential conformational changes within a CCT ring are observed, perhaps promoting domain-by-domain substrate folding. Chaperonins are implicated in bacterial infection, autoimmune disease, as well as protein aggregation and degradation diseases. Understanding the chaperonin mechanism and the specific proteins they rescue during the cell cycle is important not only for the fundamental aspect of protein folding in the cellular environment, but also for effective therapeutic strategies. 

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3. Multi-resolution simulation of DNA transport through large synthetic nanostructures

   https://doi.org/10.1039/d1cp04589j  

   Choudhary, Adnan; Maffeo, Christopher; Aksimentiev, Aleksei (February 2022, Physical Chemistry Chemical Physics)

   Modeling and simulation has become an invaluable partner in development of nanopore sensing systems. The key advantage of the nanopore sensing method – the ability to rapidly detect individual biomolecules as a transient reduction of the ionic current flowing through the nanopore – is also its key deficiency, as the current signal itself rarely provides direct information about the chemical structure of the biomolecule. Complementing experimental calibration of the nanopore sensor readout, coarse-grained and all-atom molecular dynamics simulations have been used extensively to characterize the nanopore translocation process and to connect the microscopic events taking place inside the nanopore to the experimentally measured ionic current blockades. Traditional coarse-grained simulations, however, lack the precision needed to predict ionic current blockades with atomic resolution whereas traditional all-atom simulations are limited by the length and time scales amenable to the method. Here, we describe a multi-resolution framework for modeling electric field-driven passage of DNA molecules and nanostructures through to-scale models of synthetic nanopore systems. We illustrate the method by simulating translocation of double-stranded DNA through a solid-state nanopore and a micron-scale slit, capture and translocation of single-stranded DNA in a double nanopore system, and modeling ionic current readout from a DNA origami nanostructure passage through a nanocapillary. We expect our multi-resolution simulation framework to aid development of the nanopore field by providing accurate, to-scale modeling capability to research laboratories that do not have access to leadership supercomputer facilities. 

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4. Sign Gradient Descent Algorithms for Accelerated Kinetostatic Protein Folding in Nanorobotics Design

   https://doi.org/10.3390/robotics14110167  

   Mohammadi, Alireza; Al_Janaideh, Mohammad (November 2025, Robotics)

   Numerical simulations of protein folding enable the design of protein-based nanomachines and nanorobots by predicting folded three-dimensional protein structures with high accuracy and revealing the protein conformation transitions during folding and unfolding. In the kinetostatic compliance method (KCM) for folding simulations, protein molecules are represented as ensembles of rigid nano-linkages connected by chemical bonds, and the folding process is driven by the kinetostatic influence of nonlinear interatomic force fields until the system converges to a free-energy minimum of the protein. Despite its strengths, the conventional KCM framework demands an excessive number of iterations to reach folded protein conformations, with each iteration requiring costly computations of interatomic force fields. To address these limitations, this work introduces a family of sign gradient descent (SGD) algorithms for predicting folded protein structures. Unlike the heuristic-based iterations of the conventional KCM framework, the proposed SGD algorithms rely on the sign of the free-energy gradient to guide the kinetostatic folding process. Owing to their faster and more robust convergence, the proposed SGD-based algorithms reduce the computational burden of interatomic force field evaluations required to reach folded conformations. Their effectiveness is demonstrated through numerical simulations of KCM-based folding of protein backbone chains. 

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5. Periodic splay Fréedericksz transitions in a ferroelectric nematic

   https://doi.org/10.1038/s41467-025-55827-9  

   Basnet, Bijaya; Paladugu, Sathyanarayana; Kurochkin, Oleksandr; Buluy, Oleksandr; Aryasova, Natalie; Nazarenko, Vassili G; Shiyanovskii, Sergij V; Lavrentovich, Oleg D (December 2025, Nature Communications)

   Abstract Electric field-induced splay of molecular orientation, called the Fréedericksz transition, is a fundamental electro-optic phenomenon in nonpolar nematic liquid crystals. In a ferroelectric nematic N_Fwith a spontaneous electric polarization$${{\bf{P}}}$$ $P$, the splay is suppressed since it produces bound electric charges. Here, we demonstrate that an alternating current (ac) electric field causes three patterns of N_Fpolarization. At low voltages,$${{\bf{P}}}$$ $P$oscillates around the field-free orientation with no stationary deformations. As the voltage increases, the polarization acquires stationary distortions, first splay and twist in a stripe pattern and then splay and bend in a square lattice of +1 and -1 defects. In all patterns,$${{\bf{P}}}$$ $P$oscillates around the stationary orientations. The stationary bound charge is reduced by a geometrical “splay cancellation” mechanism that does not require free ions: the charge created by splay in one plane is reduced by splay of an opposite sign in the orthogonal plane. 

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