Grid-steered molecular dynamics

Grid-steered molecular dynamics (G-SMD) is a flexible method for applying forces that our group has implemented in NAMD. Much as in experiment, simulation studies often involve perturbing the system in some way and monitoring the result. As simulations have become bigger, longer, and more complex, the need for more sophisticated forcing techniques has increased. In the G-SMD method, an arbitrary external potential field, defined on a grid, is applied to desired target atoms with arbitrary coupling, making it a very flexible tool. Because it is coded natively in NAMD, the performance impact of G-SMD is minimal. G-SMD provides tremendous flexibility in the forces that can be applied. It was originally designed to apply an enhanced electrostatic field to DNA threaded through the membrane protein α-hemolysin in order to realistically increase the DNA translocation speed. It is the basis for a method of combining crystallographic structures and cryo-EM maps to obtain an all-atom model developed by Trabuco et al. and called Molecular Dynamics Flexible Fitting (MDFF). A variation of this approach was also recently used by our group to study the mechanical properties of a complete microtubule.

Exploring transmembrane transport through alpha-hemolysin with grid-steered molecular dynamics

David B. Wells, Volha Abramkina, and Aleksei Aksimentiev J Chem Phys (2007)

The transport of biomolecules across cell boundaries is central to cellular function. While structures of many membrane channels are known, the permeation mechanism is known only for a select few. Molecular dynamics (MD) is a computational method that can provide an accurate description of permeation events at the atomic level, which is required for understanding the transport mechanism. However, due to the relatively short time scales accessible to this method, it is of limited utility. Here, we present a method for all-atom simulation of electric field-driven transport of large solutes through membrane channels, which in tens of nanoseconds can provide a realistic account of a permeation event that would require a millisecond simulation using conventional MD. In this method, the average distribution of the electrostatic potential in a membrane channel under a transmembrane bias of interest is determined first from an all-atom MD simulation. This electrostatic potential, defined on a grid, is subsequently applied to a charged solute to steer its permeation through the membrane channel. We apply this method to investigate permeation of DNA strands, DNA hairpins, and alpha-helical peptides through alpha-hemolysin. To test the accuracy of the method, we computed the relative permeation rates of DNA strands having different sequences and global orientations. The results of the G-SMD simulations were found to be in good agreement in experiment.

Mechanical properties of a complete microtubule revealed through molecular dynamics simulation

David B. Wells, and Aleksei Aksimentiev Biophys J (2010)

Microtubules (MTs) are the largest type of cellular filament, essential in processes ranging from mitosis and meiosis to flagellar motility. Many of the processes depend critically on the mechanical properties of the MT, but the elastic moduli, notably the Young's modulus, are not directly revealed in experiment, which instead measures either flexural rigidity or response to radial deformation. Molecular dynamics (MD) is a method that allows the mechanical properties of single biomolecules to be investigated through computation. Typically, MD requires an atomic resolution structure of the molecule, which is unavailable for many systems, including MTs. By combining structural information from cryo-electron microscopy and electron crystallography, we have constructed an all-atom model of a complete MT and used MD to determine its mechanical properties. The simulations revealed nonlinear axial stress-strain behavior featuring a pronounced softening under extension, a possible plastic deformation transition under radial compression, and a distinct asymmetry in response to the two senses of twist. This work demonstrates the possibility of combining different levels of structural information to produce all-atom models suitable for quantitative MD simulations, which extends the range of systems amenable to the MD method and should enable exciting advances in our microscopic knowledge of biology.

Contributing Members

Aleksei Aksimentiev

David B. Wells