Review Articles

Christopher Maffeo, Han-Yi Chou, and Aleksei Aksimentiev
Advanced Theory and Simulations 2 1800191 (2019)
DOI:10.1002/adts.201800191  BibTex

Reproduction, the hallmark of biological activity, requires making an accurate copy of the genetic material to allow the progeny to inherit parental traits. In all living cells, the process of DNA replication is carried out by a concerted action of multiple protein species forming a loose protein–nucleic acid complex, the replisome. Proofreading and error correction generally accompany replication but also occur independently, safeguarding genetic information through all phases of the cell cycle. Advances in biochemical characterization of intracellular processes, proteomics, and the advent of single-molecule biophysics have brought about a treasure trove of information awaiting to be assembled into an accurate mechanistic model of the DNA replication process. This review describes recent efforts to model elements of DNA replication and repair processes using computer simulations, an approach that has gained immense popularity in many areas of molecular biophysics but has yet to become mainstream in the DNA metabolism community. It highlights the use of diverse computational methods to address specific problems of the fields and discusses unexplored possibilities that lie ahead for the computational approaches in these areas.

Jejoong Yoo, and Aleksei Aksimentiev
Physical Chemistry Chemical Physics 20 8432-8449 (2018)
DOI:10.1039/C7CP08185E  BibTex

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—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.

Christopher Maffeo, J Yoo, Jeffrey Comer, D B. Wells, B Luan, and Aleksei Aksimentiev
J Phys Condens Matter 26(41) 413101 (2014)
DOI:10.1088/0953-8984/26/41/413101  PMID:25238560  BibTex

Over the past ten years, the all-atom molecular dynamics method has grown in the scale of both systems and processes amenable to it and in its ability to make quantitative predictions about the behavior of experimental systems. The field of computational DNA research is no exception, witnessing a dramatic increase in the size of systems simulated with atomic resolution, the duration of individual simulations and the realism of the simulation outcomes. In this topical review, we describe the hallmark physical properties of DNA from the perspective of all-atom simulations. We demonstrate the amazing ability of such simulations to reveal the microscopic physical origins of experimentally observed phenomena. We also discuss the frustrating limitations associated with imperfections of present atomic force fields and inadequate sampling. The review is focused on the following four physical properties of DNA: effective electric charge, response to an external mechanical force, interaction with other DNA molecules and behavior in an external electric field.

Maxim Belkin, Shu-Han Chao, Gino Giannetti, and Aleksei Aksimentiev
Journal of Computational Electronics 13(4) 826-838 (2014)
DOI:10.1007/s10825-014-0594-8  BibTex

Local modulation of temperature has emerged as a new mechanism for regulation of molecular transport through nanopores. Predicting the effect of such modulations on nanopore transport requires simulation protocols capable of reproducing non-uniform temperature gradients observed in experiment. Conventional molecular dynamics (MD) method typically employs a single thermostat for maintaining a uniform distribution of temperature in the entire simulation domain, and, therefore, can not model local temperature variations. In this article, we describe a set of simulation protocols that enable modeling of nanopore systems featuring non-uniform distributions of temperature. First, we describe a method to impose a temperature gradient in all-atom MD simulations based on a boundary-driven non-equilibrium MD protocol. Then, we use this method to study the effect of temperature gradient on the distribution of ions in bulk solution (the thermophoretic effect). We show that DNA nucleotides exhibit differential response to the same temperature gradient. Next, we describe a method to directly compute the effective force of a thermal gradient on a prototypical biomolecule — a fragment of double-stranded DNA. Following that, we demonstrate an all-atom MD protocol for modeling thermophoretic effects in solid-state nanopores. We show that local heating of a nanopore volume can be used to regulate the nanopore ionic current. Finally, we show how continuum calculations can be coupled to a coarse-grained model of DNA to study the effect of local temperature modulation on electrophoretic motion of DNA through plasmonic nanopores. The computational methods described in this article are expected to find applications in rational design of temperature-responsive nanopore systems.

Christopher Maffeo, Swati Bhattacharya, Jejoong Yoo, David B. Wells, and Aleksei Aksimentiev
Chem Rev 112(12) 6250-6284 (2012)
DOI:10.1021/cr3002609  PMID:23035940  BibTex

Transport of ions through pores in membranes is a process of fundamental importance to cell biology. In living organisms, such transport is facilitated by ion channels that utilize the ionic flux to perform diverse biological functions, such as cell–cell communication and signaling, osmotic stress response, muscle contraction, etc. The action of ion channels is responsible for most of what we (humans) perceive as reality in the form of sound, smell, sight, taste, and touch and forms the physiological basis for thought. Biomimetic ion channels are ubiquitous in engineering, with application ranging from water desalination to fuel cells. Here, we review efforts to model and simulate ion channels that occurred within the past 10 years.

Winston Timp, Utkur M. Mirsaidov, Deqiang Wang, Jeffrey Comer, Aleksei Aksimentiev, and Gregory Timp
IEEE Trans Nanotechnol 9(3) 281-294 (2010)
DOI:10.1109/TNANO.2010.2044418  PMID:21572978  BibTex

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.

Aleksei Aksimentiev
Nanoscale 2(4) 468-83 (2010)
DOI:10.1039/b9nr00275h  PMID:20644747  BibTex

Within just a decade from the pioneering work demonstrating the utility of nanopores for molecular sensing, nanopores have emerged as versatile systems for single-molecule manipulation and analysis. In a typical setup, a gradient of the electrostatic potential captures charged solutes from the solution and forces them to move through a single nanopore, across an otherwise impermeable membrane. The ionic current blockades resulting from the presence of a solute in a nanopore can reveal the type of the solute, for example, the nucleotide makeup of a DNA strand. Despite great success, the microscopic mechanisms underlying the functionality of such stochastic sensors remain largely unknown, as it is not currently possible to characterize the microscopic conformations of single biomolecules directly in a nanopore and thereby unequivocally establish the causal relationship between the observables and the microscopic events. Such a relationship can be determined using molecular dynamics-a computational method that can accurately predict the time evolution of a molecular system starting from a given microscopic state. This article describes recent applications of this method to the process of DNA transport through biological and synthetic nanopores.