@article {364, title = {A nanoscale reciprocating rotary mechanism with coordinated mobility control.}, journal = {Nature Communications}, volume = {12}, year = {2021}, month = {12/2021}, pages = {7138}, chapter = {7138}, abstract = {

Biological molecular motors transform chemical energy into mechanical work by coupling cyclic catalytic reactions to large-scale structural transitions. Mechanical deformation can be surprisingly efficient in realizing such coupling, as demonstrated by the FoF1 ATP synthase. Here, we describe a synthetic molecular mechanism that transforms a rotary motion of an asymmetric camshaft into reciprocating large-scale transitions in a surrounding stator orchestrated by mechanical deformation. We design the mechanism using DNA origami, characterize its structure via cryo-electron microscopy, and examine its dynamic behavior using single-particle fluorescence microscopy and molecular dynamics simulations. While the camshaft can rotate inside the stator by diffusion, the stator{\textquoteright}s mechanics makes the camshaft pause at preferred orientations. By changing the stator{\textquoteright}s mechanical stiffness, we accelerate or suppress the Brownian rotation, demonstrating an allosteric coupling between the camshaft and the stator. Our mechanism provides a framework for manufacturing artificial nanomachines that function because of coordinated movements of their components.

}, keywords = {Cryoelectron Microscopy, DNA, Molecular Conformation, Molecular Dynamics Simulation, Nanostructures, Nanotechnology, Rotation}, issn = {2041-1723}, doi = {10.1038/s41467-021-27230-7}, author = {Bertosin, Eva and Maffeo, Christopher M and Drexler, Thomas and Honemann, Maximilian N and Aleksei Aksimentiev and Dietz, Hendrik} } @article {367, title = {Netting proteins, one at a time}, journal = {Nature Nanotechnology}, volume = {16}, year = {2021}, month = {01/2021}, pages = {1178 - 1179}, abstract = {

Ever tried catching fish by hand? Fast and slippery, the fish easily escapes {\textemdash}unless, of course, the hand is holding a fishing net. Catching single proteins has been an outstanding technological challenge because of their small size (about 10 nm) and the stochastic Brownian forces that dominate protein motion at the nanoscale. Methods have been devised to adsorb proteins onto surfaces or to target specific proteins for analysis using antibodies, but such approaches typically produce permanent attachment of the proteins to their macroscopic handles. Writing in Nature Nanotechnology, Schmid and co-workers report a catch-and-release nanopore trap capable of holding single proteins for hours, giving ample time for single-molecule characterization of the protein shape.

}, issn = {1748-3387}, doi = {10.1038/s41565-021-00968-3}, url = {https://www.nature.com/articles/s41565-021-00968-3https://www.nature.com/articles/s41565-021-00968-3.pdfhttps://www.nature.com/articles/s41565-021-00968-3.pdfhttps://www.nature.com/articles/s41565-021-00968-3}, author = {Aleksei Aksimentiev} } @article {282, title = {New tricks for old dogs: Improving the accuracy of biomolecular force fields by pair-specific corrections to non-bonded interactions}, journal = {Physical Chemistry Chemical Physics}, volume = {20}, year = {2018}, month = {03/2018}, pages = {8432-8449}, abstract = {

In contrast to ordinary polymers, the vast majority of biological macromolecules adopt highly ordered three-dimensional structures that define their functions. The key to folding of a biopolymer into a unique 3D structure or to assembly of several biopolymers into a functional unit is a delicate balance between the attractive and repulsive forces that also makes such self-assembly reversible under physiological conditions. The all-atom molecular dynamics (MD) method has emerged as a powerful tool for studies of individual biomolecules and their functional assemblies, encompassing systems of ever increasing complexity. However, advances in parallel computing technology have outpaced development of the underlying theoretical models{\textemdash}the molecular force fields, pushing the MD method into untested territory. Recent tests of the MD method have found the most commonly used molecular force fields to be out of balance, overestimating attractive interactions between charged and hydrophobic groups, which can promote artificial aggregation in MD simulations of multi-component protein, nucleic acid, and lipid systems. One route to improving the force fields is through the NBFIX corrections method, in which the intermolecular forces are calibrated against experimentally measured quantities such as osmotic pressure by making atom pair-specific adjustments to the non-bonded interactions. In this article, we review development of the NBFIX corrections to the AMBER and CHARMM force fields and discuss their implications for MD simulations of electrolyte solutions, dense DNA systems, Holliday junctions, protein folding, and lipid bilayer membranes.

}, doi = {10.1039/C7CP08185E}, author = {Jejoong Yoo and Aleksei Aksimentiev} } @article {268, title = {Nanoscale Ion Pump Derived from a Biological Water Channel}, journal = {The Journal of Physical Chemistry B }, volume = {121}, year = {2017}, month = {08/2017}, pages = {7899{\textendash}7906 }, abstract = {

Biological molecular machines perform the\ work of supporting life at the smallest of scales, including\ the work of shuttling ions across cell boundaries and against\ chemical gradients. Systems of artifi cial channels at the\ nanoscale can likewise control ionic concentration by way of\ ionic current rectifi cation, species selectivity, and voltage\ gating mechanisms. Here, we theoretically show that a voltagegated,\ ion species-selective, and rectifying ion channel can be\ built using the components of a biological water channel\ aquaporin. Through all-atom molecular dynamics simulations,\ we show that the ionic conductance of a truncated aquaporin\ channel nonlinearly increases with the bias magnitude, depends on the channel{\textquoteright} s orientation, and is highly cation specific but only\ for one polarity of the transmembrane bias. Further, we show that such an unusually complex response of the channel to\ transmembrane bias arises from mechanical motion of a positively charged gate that blocks cation transport. By combining two\ truncated aquaporins, we demonstrate a molecular system that pumps ions against their chemical gradients when subject to an\ alternating transmembrane bias. Our work sets the stage for future biomimicry eff orts directed toward reproducing the function\ of biological ion pumps using synthetic components.

}, doi = {10.1021/acs.jpcb.7b05568}, author = {Karl Decker and Martin Page and Aleksei Aksimentiev} } @article {270, title = {Nanopore Sensing of Protein Folding}, journal = {ACS Nano}, volume = {11, 7091-7100}, year = {2017}, month = {05/2017}, abstract = {

Single-molecule studies of protein folding\ hold keys to unveiling protein folding pathways and elusive intermediate folding states-attractive pharmaceutical targets. Although conventional single-molecule approaches can detect folding intermediates, they presently lack throughput and require elaborate labeling. Here, we theoretically show that measurements of ionic current through a nanopore containing a protein can report on the protein{\textquoteright}s folding state. Our all-atom molecular dynamics (MD) simulations show that the unfolding of a protein lowers the nanopore ionic current, an effect that originates from the reduction of ion mobility in proximity to a protein. Using a theoretical model, we show that the average change in ionic current produced by a folding-unfolding transition is detectable despite the orientational and conformational heterogeneity of the folded and unfolded states. By analyzing millisecond-long all-atom MD simulations of multiple protein transitions, we show that a nanopore ionic current recording can detect folding-unfolding transitions in real time and report on the structure of folding intermediates.

}, doi = {10.1021/acsnano.7b02718}, url = {http://pubs.acs.org/doi/abs/10.1021/acsnano.7b02718}, author = {Si, Wei and Aleksei Aksimentiev} } @article {32, title = {Nanopore analysis of individual RNA/antibiotic complexes.}, journal = {ACS Nano}, volume = {5}, year = {2011}, month = {2011 Dec 27}, pages = {9345-53}, abstract = {

Nanopores in thin solid-state membranes are used to rapidly analyze individual RNA/drug complexes. The interactions of a truncated A-site RNA model of the prokaryotic ribosome with aminoglycoside antibiotics are characterized by passing individual molecules through a 3-3.5 nm diameter pore fabricated in a 8-10 nm thick silicon nitride membrane. Complexes of the A-site RNA with aminoglycosides can be distinguished from unbound A-site based on the ion current signatures produced as they pass through the nanopores. Counting the fraction of free and drug-bound molecules affords label-free drug-RNA binding isotherms consistent with literature reports and with data generated using independent fluorescence-based assays. Our measurements are supported by molecular dynamics simulations, which illustrate the relationship between the ionic current and complexation of the A-site RNA with paramomycin, a prototypical aminoglycoside antibiotic.

}, keywords = {Anti-Bacterial Agents, Binding Sites, Diffusion, Electroporation, Materials Testing, Membranes, Artificial, Nanostructures, Paromomycin, Porosity, RNA, Semiconductors}, issn = {1936-086X}, doi = {10.1021/nn203764j}, author = {Meni Wanunu and Bhattacharya, Swati and Xie, Yun and Tor, Yitzhak and Aleksei Aksimentiev and Drndic, Marija} } @inbook {193, title = {Nanopore Force Spectroscopy: Insights from Molecular Dynamics Simulations}, booktitle = {Nanopores: Sensing and Fundamental Biological Interactions}, year = {2011}, pages = {335{\textendash}356}, publisher = {Springer Science and Business Media, LLC}, organization = {Springer Science and Business Media, LLC}, chapter = {14}, address = {New York}, abstract = {

Nanopore force spectroscopy (NFS) has emerged as a convenient method to characterize the behavior of single biomolecules and biomolecular assemblies under force. NFS has many advantages over conventional single molecule techniques, such as being label-free and high throughput; however, NFS lacks direct control over the force applied to the biomolecules and registers the conformational transitions induced by the force only indirectly, by monitoring changes in the ionic current passing through the pore. In this chapter, we describe how all-atom molecular dynamics simulations can complement NFS experiments by providing information inaccessible to experiment. The chapter illustrates applications of the molecular dynamics (MD) method to interpret the results of NFS measurements, characterize the forces involved and determine the microscopic origin of the observed phenomena. Important technical aspects of the method, as well as its pitfalls and limitations are briefly discussed.

}, isbn = {978-144-198-2-5-1-3}, doi = {10.1007/978-1-4419-8252-0_14}, author = {Jeffrey Comer and Aleksei Aksimentiev}, editor = {Rashid Bashir and Samir Iqbal} } @article {36, title = {Nanopore Sequencing: Electrical Measurements of the Code of Life}, journal = {IEEE Trans Nanotechnol}, volume = {9}, year = {2010}, month = {2010 May 1}, pages = {281-294}, abstract = {

Sequencing a single molecule of deoxyribonucleic acid (DNA) using a nanopore is a revolutionary concept because it combines the potential for long read lengths (\>5 kbp) with high speed (1 bp/10 ns), while obviating the need for costly amplification procedures due to the exquisite single molecule sensitivity. The prospects for implementing this concept seem bright. The cost savings from the removal of required reagents, coupled with the speed of nanopore sequencing places the $1000 genome within grasp. However, challenges remain: high fidelity reads demand stringent control over both the molecular configuration in the pore and the translocation kinetics. The molecular configuration determines how the ions passing through the pore come into contact with the nucleotides, while the translocation kinetics affect the time interval in which the same nucleotides are held in the constriction as the data is acquired. Proteins like α-hemolysin and its mutants offer exquisitely precise self-assembled nanopores and have demonstrated the facility for discriminating individual nucleotides, but it is currently difficult to design protein structure ab initio, which frustrates tailoring a pore for sequencing genomic DNA. Nanopores in solid-state membranes have been proposed as an alternative because of the flexibility in fabrication and ease of integration into a sequencing platform. Preliminary results have shown that with careful control of the dimensions of the pore and the shape of the electric field, control of DNA translocation through the pore is possible. Furthermore, discrimination between different base pairs of DNA may be feasible. Thus, a nanopore promises inexpensive, reliable, high-throughput sequencing, which could thrust genomic science into personal medicine.

}, keywords = {Review}, issn = {1536-125X}, doi = {10.1109/TNANO.2010.2044418}, author = {Timp, Winston and Mirsaidov, Utkur M and Wang, Deqiang and Jeffrey Comer and Aleksei Aksimentiev and Gregory Timp} }