@article {285, title = {Inchworm movement of two rings switching onto a thread by biased Brownian diffusion represent a three-body problem}, journal = {Proceedings of the National Academy of Sciences}, year = {2018}, month = {05/2018}, abstract = {

This article describes a molecular realization of the classical three-body problem, where the motion of three or more bodies is directed by a set of pairwise forces. Surprisingly, motion of the components of the three-body molecular systems is found to be highly choreographed by differences in strength of intercomponent interactions, promoting a rare inchworm-like loading of molecular rings onto a molecular thread. Our work demonstrates the utility of an integrative approach to design and develop functional molecular machines.The coordinated motion of many individual components underpins the operation of all machines. However, despite generations of experience in engineering, understanding the motion of three or more coupled components remains a challenge, known since the time of Newton as the {\textquotedblleft}three-body problem.{\textquotedblright} Here, we describe, quantify, and simulate a molecular three-body problem of threading two molecular rings onto a linear molecular thread. Specifically, we use voltage-triggered reduction of a tetrazine-based thread to capture two cyanostar macrocycles and form a [3]pseudorotaxane product. As a consequence of the noncovalent coupling between the cyanostar rings, we find the threading occurs by an unexpected and rare inchworm-like motion where one ring follows the other. The mechanism was derived from controls, analysis of cyclic voltammetry (CV) traces, and Brownian dynamics simulations. CVs from two noncovalently interacting rings match that of two covalently linked rings designed to thread via the inchworm pathway, and they deviate considerably from the CV of a macrocycle designed to thread via a stepwise pathway. Time-dependent electrochemistry provides estimates of rate constants for threading. Experimentally derived parameters (energy wells, barriers, diffusion coefficients) helped determine likely pathways of motion with rate-kinetics and Brownian dynamics simulations. Simulations verified intercomponent coupling could be separated into ring{\textendash}thread interactions for kinetics, and ring{\textendash}ring interactions for thermodynamics to reduce the three-body problem to a two-body one. Our findings provide a basis for high-throughput design of molecular machinery with multiple components undergoing coupled motion.

}, issn = {0027-8424}, doi = {10.1073/pnas.1719539115}, url = {http://www.pnas.org/content/early/2018/05/03/1719539115}, author = {Benson, Christopher R. and Maffeo, Christopher and Fatila, Elisabeth M. and Liu, Yun and Sheetz, Edward G. and Aleksei Aksimentiev and Singharoy, Abhishek and Flood, Amar H.} } @article {253, title = {Interference-free detection of genetic biomarkers using synthetic dipole-facilitated nanopore dielectophoresis.}, journal = {ACS Nano}, volume = {11}, year = {2017}, month = {01/2017}, pages = {1204-1213}, chapter = {1204}, abstract = {

The motion of polarizable particles in a non-uniform electric field, i.e., dielectrophoresis, has been extensively used for concentration, separation, sorting, and transport of biological particles, from cancer cells and viruses to biomolecules such as DNAs and proteins. However, current approaches to dielectrophoretic manipulation are not sensitive enough to selectively target individual molecular species. Here we describe the application of the dielectrophoretic principle for selective detection of DNA and RNA molecules using an engineered biological nanopore. The key element of our approach is a synthetic polycationic nanocarrier that selectively binds to the target biomolecules, dramatically increasing their dielectrophoretic response to the electric field gradient generated by the nanopore. The dielectrophoretic capture of the nanocarrier-target complexes is detected as a transient blockade of the nanopore ionic current while any non-target nucleic acids are repelled from the nanopore by electrophoresis and thus do not interfere with the signal produced by the target{\textquoteright}s capture. Strikingly, we show that even modestly charged nanocarriers can be used to capture DNA or RNA molecules of any length or secondary structure and simultaneously detect several molecular targets. Such selective, multiplex molecular detection technology would be highly desirable for real-time analysis of complex clinical samples.

}, doi = {10.1021/acsnano.6b07570}, author = {Kai Tian and Karl Decker and Aleksei Aksimentiev and Li-Qun Gu} } @article {218, title = {Improved model of hydrated calcium ion for molecular dynamics simulations using classical biomolecular force fields}, journal = {Biopolymers}, volume = {105}, year = {2016}, month = {07/2016}, pages = {752-763}, chapter = {752}, abstract = {
Calcium ions (Ca2+) play key roles in various fundamental biological processes such as cell signaling and brain function . Molecular dynamics (MD) simulations have been used to study such interactions, however, the accuracy of the Ca2+ models provided by the standard M D force fields has not been rigorously tested. Here, we assess the performance of the Ca2+ models from the most popular classical force fields AMBER and CHARMM by computing the osmotic pressure of model compounds and the free energy of DNA{\textendash}DNA inter act i on s. In the simulations performed using the two standard models, Ca2+ ions are seen to form artificial clusters with chloride, acetate, and phosphate species; the osmotic pressure of CaAc2and CaCl2solutions is a small fraction of the experimental values for both force fields. Using the standard parameterization of Ca2+ ions in the simulations of Ca2+-mediated DNA-DNA interact ions leads to qualitatively wrong outcomes: both AMBER and CHARMM simulations suggest strong inter-DNA attraction whereas, in experiment, DNA molecules repel one another. The artificial attraction of Ca2+to DNA phosphate is strong enough to affect the direction of the electric field-driven translocation of DNA through a solid-state nanopore. To address these shortcomings of the standard Ca2+ model, we introduce a custom model of a hydrated Ca2+ ion and show that using our model brings the results of the above MD simulations in quantitative agreement with experiment. Our improved model of Ca2+ can be readily applied to MD simulations of various biomolecular systems, including nucleic acids, proteins and lipid bilayer membranes.
}, doi = {10.1002/bip.22868}, author = {Jejoong Yoo and James Wilson and Aleksei Aksimentiev} } @article {236, title = {Ion Channels Made from a Single Membrane-Spanning DNA Duplex}, journal = {Nano Letters}, volume = {16}, year = {2016}, month = {06/2016}, pages = {4665--4669}, abstract = {

Due to their hollow interior, transmembrane channels are capable of opening up pathways for ions across lipid membranes of living cells. Here, we demonstrate ion conduction induced by a single DNA duplex that lacks a hollow central channel. Decorated with six porpyrin-tags, our duplex is designed to span lipid membranes. Combining electrophysiology measurements with all-atom molecular dynamics simulations, we elucidate the microscopic conductance pathway\ (see\ water channel\ trajectory, require login to nanoHUB). Ions flow (see ion transport\ trajectory)\ at the DNA-lipid interface as the lipid head groups tilt towards the amphiphilic duplex forming a toroidal pore filled with water and ions. Ionic current traces produced by the DNA-lipid channel show well-defined insertion steps, closures and gating similar to those observed for traditional protein channels or synthetic pores. Ionic conductances obtained through simulations and experiments are in excellent quantitative agreement. The conductance mechanism realized here, with the smallest possible DNA-based ion channel, offers a route to design a new class of synthetic ion channels with maximum simplicity.

}, doi = {10.1021/acs.nanolett.6b02039}, author = {Kerstin G{\"o}pfrich and Chen-Yu Li and Iwona Mames and Satya Prathyusha Bhamidimarri and Maria Ricci and Jejoong Yoo and Adam Mames and Alexander Ohmann and Mathias Winterhalter and Eugen Stulz and Aleksei Aksimentiev and Ulrich F Keyser} } @article {209, title = {Improved Parameterization of Amine{\textendash}Carboxylate and Amine{\textendash}Phosphate Interactions for Molecular Dynamics Simulations Using the CHARMM and AMBER Force Fields}, journal = {Journal of Chemical Theory and Computation}, volume = {12}, year = {2016}, pages = {430{\textendash}443}, abstract = {

Over the past decades, molecular dynamics (MD) simulations of biomolecules have become a mainstream biophysics technique. As the length and time scales amenable to the MD method increase, shortcomings of the empirical force fields, which have been developed and validated using relatively short simulations of small molecules, become apparent. One common artifact is aggregation of water-soluble biomolecules driven by artificially strong charge{\textendash}charge interactions. Here, we report a systematic atom pair-specific refinement of Lennard-Jones parameters (NBFIX) describing amine{\textendash}carboxylate and amine{\textendash}phosphate interactions, which bring MD simulations of basic peptide-mediated nucleic acid assemblies and lipid bilayer membranes into better agreement with experimental data. As our refinement does not affect the existing parametrization of bonded interactions or alter the solvation free energies, it improves the realism of an MD simulation without introducing additional artifacts.

}, doi = {10.1021/acs.jctc.5b00967}, author = {Jejoong Yoo and Aleksei Aksimentiev} } @article {LI2015, title = {Ionic Conductivity, Structural Deformation, and Programmable Anisotropy of DNA Origami in Electric Field}, journal = {ACS Nano}, volume = {9}, year = {2015}, note = {PMID: 25623807}, month = {01/2015}, pages = {1420-1433}, abstract = {

The DNA origami technique can enable functionalization of inorganic structures for single-molecule electric current recordings. Experiments have shown that several layers of DNA molecules, a DNA origami plate, placed on top of a solid-state nanopore is permeable to ions. Here, we report a comprehensive characterization of the ionic conductivity of DNA origami plates by means of all-atom molecular dynamics (MD) simulations and nanocapillary electric current recordings. Using the MD method, we characterize the ionic conductivity of several origami constructs, revealing the local distribution of ions, the distribution of the electrostatic potential and contribution of different molecular species to the current. The simulations determine the dependence of the ionic conductivity on the applied voltage, the number of DNA layers, the nucleotide content and the lattice type of the plates. We demonstrate that increasing the concentration of Mg2+\ ions makes the origami plates more compact, reducing their conductivity. The conductance of a DNA origami plate on top of a solid-state nanopore is determined by the two competing effects: bending of the DNA origami plate that reduces the current and separation of the DNA origami layers that increases the current. The latter is produced by the electro-osmotic flow and is reversible at the time scale of a hundred nanoseconds. The conductance of a DNA origami object is found to depend on its orientation, reaching maximum when the electric field aligns with the direction of the DNA helices. Our work demonstrates feasibility of programming the electrical properties of a self-assembled nanoscale object using DNA.

}, doi = {10.1021/nn505825z}, url = {http://dx.doi.org/10.1021/nn505825z}, author = {Li, Chen-Yu and Hemmig, Elisa A. and Kong, Jinglin and Yoo, Jejoong and Hern{\'a}ndez-Ainsa, Silvia and Keyser, Ulrich F. and Aleksei Aksimentiev} } @article {90, title = {In situ structure and dynamics of DNA origami determined through molecular dynamics simulations.}, journal = {Proc Natl Acad Sci U S A}, volume = {110}, year = {2013}, month = {12/2013}, pages = {20099-104}, abstract = {

The DNA origami method permits folding of long single-stranded DNA into complex 3D structures with subnanometer precision. Transmission electron microscopy, atomic force microscopy, and recently cryo-EM tomography have been used to characterize the properties of such DNA origami objects, however their microscopic structures and dynamics have remained unknown. Here, we report the results of all-atom molecular dynamics simulations that characterized the structural and mechanical properties of DNA origami objects in unprecedented microscopic detail. When simulated in an aqueous environment, the structures of DNA origami objects depart from their idealized targets as a result of steric, electrostatic, and solvent-mediated forces. Whereas the global structural features of such relaxed conformations conform to the target designs, local deformations are abundant and vary in magnitude along the structures. In contrast to their free-solution conformation, the Holliday junctions in the DNA origami structures adopt a left-handed antiparallel conformation. We find the DNA origami structures undergo considerable temporal fluctuations on both local and global scales. Analysis of such structural fluctuations reveals the local mechanical properties of the DNA origami objects. The lattice type of the structures considerably affects global mechanical properties such as bending rigidity. Our study demonstrates the potential of all-atom molecular dynamics simulations to play a considerable role in future development of the DNA origami field by providing accurate, quantitative assessment of local and global structural and mechanical properties of DNA origami objects.

}, keywords = {DNA, Single-Stranded, Models, Molecular, Molecular Dynamics Simulation, Nanotechnology, Nucleic Acid Conformation, Water}, issn = {1091-6490}, doi = {10.1073/pnas.1316521110}, author = {Yoo, Jejoong and Aleksei Aksimentiev} } @article {91, title = {Improved Parametrization of Li+, Na+, K+, and Mg2+ Ions for All-Atom Molecular Dynamics Simulations of Nucleic Acid Systems}, journal = {The Journal of Physical Chemistry Letters}, volume = {3}, year = {2012}, pages = {45-50}, abstract = {

Atomic-scale modeling of compacted nucleic acids has the ability to reveal the inner workings of spectacular biomolecular machines, yet the outcome of such modeling efforts sensitively depends on the accuracy of the underlying computational models. Our molecular dynamics simulations of an array of 64 parallel duplex DNA revealed considerable artifacts of cation-DNA phosphate interactions in CHARMM and AMBER parameter sets: both the DNA arrangement and the pressure inside the DNA arrays were found to be in considerable disagreement with experiment. To improve the models, we fine-tuned van der Waals interaction parameters for specific ion pairs to reproduce experimental osmotic pressure of binary electrolyte solutions of biologically relevant ions. Repeating the DNA array simulations using our parameters produced results consistent with experiment. Our improved parametrization can be directly applied to molecular dynamics simulations of various charged biomolecular systems, including nucleic acids, proteins, and lipid bilayer membranes.

}, issn = {1948-7185}, doi = {10.1021/jz201501a}, url = {http://pubs.acs.org/doi/abs/10.1021/jz201501a}, author = {Yoo, Jejoong and Aleksei Aksimentiev} } @article {45, title = {Ionic Current Rectification Through Silica Nanopores}, journal = {J Phys Chem C Nanomater Interfaces}, volume = {113}, year = {2009}, month = {2009 Feb 1}, pages = {1850}, abstract = {

Nanopores immersed in electrolytic solution and under the influence of an electric field can produce ionic current rectification, where ionic currents are higher for one voltage polarity than for the opposite polarity, resulting in an asymmetric current-voltage (I-V) curve. This behavior has been observed in polymer and silicon-based nanopores as well as in theoretically studied continuum models. By means of atomic level molecular dynamics (MD) simulations, we have performed a systematic investigation of KCl conductance in silica nanopores with a total simulation time of 680 ns. We found that ion-binding spots at the silica surfaces, such as dangling atoms, have effects on the ion concentration and electrostatic potential inside the nanopore, producing asymmetric I-V curves. Conversely, silica surfaces without ion-binding spots produce symmetric I-V curves.

}, issn = {1932-7447}, doi = {10.1021/jp804724p}, author = {Eduardo Cruz-Ch{\'u} and Aleksei Aksimentiev and Klaus Schulten} } @article {61, title = {In meso crystal structure and docking simulations suggest an alternative proteoglycan binding site in the OpcA outer membrane adhesin}, journal = {Proteins}, volume = {71}, year = {2008}, month = {2008 Apr}, pages = {24-34}, abstract = {

OpcA is an integral outer membrane adhesin protein from Neisseria meningitidis, the causative agent of meningococcal meningitis and septicemia. It binds to sialic acid (SA)-containing polysaccharides on the surface of epithelial cells. The crystal structure of OpcA showed that the protein adopts a 10-stranded beta-barrel structure, with five extensive loop regions on the extracellular side of the membrane. These form a crevice structure, lined with basic residues, which was hypothesized to act as the binding site for polysaccharide ligands. In the current study, a distinctly different OpcA structure has been obtained using crystals grown from a lipidic mesophase. Comparison of the two structures shows that the largest loop (L2), which closes over the end of the beta-barrel in the original crystal form, adopts a much more extended structure by reaching outward and away from the protein. The difference in conformation may be attributable to the absence of zinc ions from the crystallization conditions for the in meso crystal form: in the original structure, two zinc ions were bound to the external loops. Molecular dynamics (MD) simulations performed on the two OpcA models in a lipid bilayer environment demonstrated pronounced loop mobility. These observations support the view that the loop regions of OpcA are capable of a high degree of conformational flexibility. The original binding site for polysaccharide is not present in the in meso crystal form, and is disrupted during MD simulations. Docking analysis suggests a putative alternative location for the SA ligand in the new crystal form of OpcA.

}, keywords = {Adhesins, Bacterial, Bacterial Outer Membrane Proteins, Binding Sites, Computer Simulation, Crystallography, X-Ray, Models, Molecular, Neisseria meningitidis, Protein Binding, Proteoglycans, Spectrum Analysis}, issn = {1097-0134}, doi = {10.1002/prot.21841}, author = {Cherezov, Vadim and Liu, Wei and Derrick, Jeremy P and Luan, Binquan and Aleksei Aksimentiev and Katritch, Vsevolod and Caffrey, Martin} } @article {72, title = {Imaging alpha-hemolysin with molecular dynamics: ionic conductance, osmotic permeability, and the electrostatic potential map}, journal = {Biophys J}, volume = {88}, year = {2005}, month = {2005 Jun}, pages = {3745-61}, abstract = {

alpha-Hemolysin of Staphylococcus aureus is a self-assembling toxin that forms a water-filled transmembrane channel upon oligomerization in a lipid membrane. Apart from being one of the best-studied toxins of bacterial origin, alpha-hemolysin is the principal component in several biotechnological applications, including systems for controlled delivery of small solutes across lipid membranes, stochastic sensors for small solutes, and an alternative to conventional technology for DNA sequencing. Through large-scale molecular dynamics simulations, we studied the permeability of the alpha-hemolysin/lipid bilayer complex for water and ions. The studied system, composed of approximately 300,000 atoms, included one copy of the protein, a patch of a DPPC lipid bilayer, and a 1 M water solution of KCl. Monitoring the fluctuations of the pore structure revealed an asymmetric, on average, cross section of the alpha-hemolysin stem. Applying external electrostatic fields produced a transmembrane ionic current; repeating simulations at several voltage biases yielded a current/voltage curve of alpha-hemolysin and a set of electrostatic potential maps. The selectivity of alpha-hemolysin to Cl(-) was found to depend on the direction and the magnitude of the applied voltage bias. The results of our simulations are in excellent quantitative agreement with available experimental data. Analyzing trajectories of all water molecule, we computed the alpha-hemolysin{\textquoteright}s osmotic permeability for water as well as its electroosmotic effect, and characterized the permeability of its seven side channels. The side channels were found to connect seven His-144 residues surrounding the stem of the protein to the bulk solution; the protonation of these residues was observed to affect the ion conductance, suggesting the seven His-144 to comprise the pH sensor that gates conductance of the alpha-hemolysin channel.

}, keywords = {Bacterial Toxins, Biophysical Phenomena, Biophysics, Computer Simulation, Electric Conductivity, Hemolysin Proteins, Hydrogen-Ion Concentration, Ion Channels, Lipid Bilayers, Models, Biological, Models, Molecular, Osmosis, Permeability, Static Electricity, Thermodynamics, Water}, issn = {0006-3495}, doi = {10.1529/biophysj.104.058727}, author = {Aleksei Aksimentiev and Klaus Schulten} } @article {76, title = {Insights into the molecular mechanism of rotation in the Fo sector of ATP synthase}, journal = {Biophys J}, volume = {86}, year = {2004}, month = {2004 Mar}, pages = {1332-44}, abstract = {

F(1)F(o)-ATP synthase is a ubiquitous membrane protein complex that efficiently converts a cell{\textquoteright}s transmembrane proton gradient into chemical energy stored as ATP. The protein is made of two molecular motors, F(o) and F(1), which are coupled by a central stalk. The membrane unit, F(o), converts the transmembrane electrochemical potential into mechanical rotation of a rotor in F(o) and the physically connected central stalk. Based on available data of individual components, we have built an all-atom model of F(o) and investigated through molecular dynamics simulations and mathematical modeling the mechanism of torque generation in F(o). The mechanism that emerged generates the torque at the interface of the a- and c-subunits of F(o) through side groups aSer-206, aArg-210, and aAsn-214 of the a-subunit and side groups cAsp-61 of the c-subunits. The mechanism couples protonation/deprotonation of two cAsp-61 side groups, juxtaposed to the a-subunit at any moment in time, to rotations of individual c-subunit helices as well as rotation of the entire c-subunit. The aArg-210 side group orients the cAsp-61 side groups and, thereby, establishes proton transfer via aSer-206 and aAsn-214 to proton half-channels, while preventing direct proton transfer between the half-channels. A mathematical model proves the feasibility of torque generation by the stated mechanism against loads typical during ATP synthesis; the essential model characteristics, e.g., helix and subunit rotation and associated friction constants, have been tested and furnished by steered molecular dynamics simulations.

}, keywords = {Binding Sites, Cell Membrane, Computer Simulation, Dimerization, Models, Chemical, Models, Molecular, Models, Statistical, Molecular Motor Proteins, Protein Binding, Protein Conformation, Protein Subunits, Proton-Translocating ATPases, Rotation, Stochastic Processes}, issn = {0006-3495}, doi = {10.1016/S0006-3495(04)74205-8}, author = {Aleksei Aksimentiev and Ilya A Balabin and Fillingame, Robert H and Klaus Schulten} } @article {80, title = {Influence of the free-energy functional form on simulated morphology of spinodally decomposing blends}, journal = {Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics}, volume = {62}, year = {2000}, month = {2000 Nov}, pages = {6821-30}, abstract = {

The spinodal decomposition of a binary mixture has been studied within several mesoscopic models. It has been found that the form of the equilibrium free energy has a crucial effect on the morphological development in asymmetric blends. We have shown that the principal quantity that determines the topology of the interface (and type of morphology) is the equilibrium minority phase volume fraction, while the transition from bicontinuous to droplet morphology can be treated as a percolation. The concentration dependence of the square gradient coefficient attributed for the Flory-Huggins-de Gennes free energy has no significant influences on the average domain growth, but can be distinguished experimentally from its constant-coefficient alternative by measuring the maximum wave vector of the scattering intensity as a function of the minority phase volume fraction for spinodally decomposing asymmetric blends. The concentration dependence of the Onsager coefficient has the weak, systematic effect of slowing down the morphological development. The local shape of the interface is not affected considerably by the concentration dependence of the square gradient and Onsager coefficient.

}, issn = {1063-651X}, author = {Aleksei Aksimentiev and Robert Ho{\l}yst} }