Simulations of biological ion channels by molecular dynamics

2004

The goal of this review is to establish a broad and rigorous theoretical framework to describe ion permeation through biological channels. This framework is developed in the context of atomic models on the basis of the statistical mechanical projection-operator formalism of Mori and Zwanzig. The review is divided into two main parts. The first part introduces the fundamental concepts needed to construct a hierarchy of dynamical models at different level of approximation. In particular, the potential of mean force (PMF) as a configuration-dependent free energy is introduced, and its significance concerning equilibrium and non-equilibrium phenomena is discussed. In addition, fundamental aspects of membrane electrostatics, with a particular emphasis on the influence of the transmembrane potential, as well as important computational techniques for extracting essential information from all-atom molecular dynamics (MD) simulations are described and discussed. The first part of the review provides a theoretical formalism to 'translate ' the information from the atomic structure into the familiar language of phenomenological models of ion permeation. The second part is aimed at reviewing and contrasting results obtained in recent computational studies of three very different channels : the gramicidin A (gA) channel, which is a narrow one-ion pore (at moderate concentration), the KcsA channel from Streptomyces lividans, which is a narrow multi-ion pore, and the outer membrane matrix porin F (OmpF) from Escherichia coli, which is a trimer of three b-barrel subunits each forming wide aqueous multi-ion pores. Comparison with experiments demonstrates that current computational models are approaching semi-quantitative accuracy and are able to provide significant insight into the microscopic mechanisms of ion conduction and selectivity. We conclude that all-atom MD with explicit water molecules can represent important structural features of complex biological channels accurately, including such features as the location of ion-binding sites along the permeation pathway. We finally discuss the broader issue of the validity of ion permeation models and an outlook to the future.

Journal of Computational Electronics, 2003

In this work, a self-consistent Langevin dynamics simulator will be presented, and computational issues unique to the simulation of charge transport through ion channels will be addressed. The simulation approach is divided into two parts; the first is the development of an efficient model to account for the charge transport in bulk electrolyte solutions, while the second is the accurate representation of the channel protein and lipid structure. A cavity is made in the interior of a phospholipid bilayer and an ion channel is inserted, where the atomic coordinates of the protein are obtained from experimental work. The electrostatic potential felt by a potassium ion along the center of the channel is then calculated and comparisons are made between two types of potassium channels, KcsA and MthK.

Biophysical Journal, 1987

The structure and dynamics of solvated alkali metal cations in transmembrane channels are treated using the molecular dynamics simulation technique. The simulations are based on a modified Fischer-Brickmann model (Fischer, W., and J. Brickmann, 1983, Biophys. Chem., 18:323-337) for gramicidin A-type channels. The trajectories of all particles in the channel as well as two-dimensional pair correlation functions are analyzed. It is found from the analysis of the stationary simulation state that one-dimensional solvation complexes are formed and that the number of water molecules in the channel varies for different alkali metal cations. Dr. Skerra's present address is Zentrum fur Gentechnologie, Am Klopferspitz, D-8033 Martinsried, FRG.

Biophysical Journal, 1998

A molecular dynamics simulation has been performed on a synthetic membrane-spanning ion channel, consisting of four ␣-helical peptides, each of which is composed of the amino acids leucine (L) and serine (S), with the sequence Ac-(LSLLLSL) 3-CONH 2. This four-helix bundle has been shown experimentally to act as a proton-conducting channel in a membrane environment. In the present simulation, the channel was initially assembled as a parallel bundle in the octane portion of a phase-separated water/octane system, which provided a membrane-mimetic environment. An explicit reversible multiple-time-step integrator was used to generate a dynamical trajectory, a few nanoseconds in duration for this composite system on a parallel computer, under ambient conditions. After more than 1 ns, the four helices were found to adopt an associated dimer state with twofold symmetry, which evolved into a coiled-coil tetrameric structure with a left-handed twist. In the coiled-coil state, the polar serine side chains interact to form a layered structure with the core of the bundle filled with H 2 O. The dipoles of these H 2 O molecules tended to align opposite the net dipole of the peptide bundle. The calculated dipole relaxation function of the pore H 2 O molecules exhibits two reorientation times. One is ϳ3.2 ps, and the other is ϳ100 times longer. The diffusion coefficient of the pore H 2 O is about one-third of the bulk H 2 O value. The total dipole moment and the inertia tensor of the peptide bundle have been calculated and reveal slow (300 ps) collective oscillatory motions. Our results, which are based on a simple united atom force-field model, suggest that the function of this synthetic ion channel is likely inextricably coupled to its dynamical behavior.

Materials Today: Proceedings, 2016

Ion channels are naturally occurring proteins that form hole in membrane. They play multiple roles in many important biological processes. Deletion or alteration of these channels often leads to serious problems in the physiological processes as it controls the flow of ions through it. The proper maintenance of the flow of ions, in turn, is required for normal health. The role of ions channels are now a proved factor behind nerve impulse. Here we have analyzed the nerve ion channel protein, with PDB entry 1BL8, which is basically an ion channel protein in Streptomyces Lividans. The equilibrium energy as well as molecular dynamics simulation is performed first. The possibility of ligand binding is investigated. The change of channel structure is found to be dependent on ligand binding. Implicit water model of the protein is subjected to molecular dynamics simulation to find their energy minimized value. Simulation of the protein in the environment of water and ions has given us important results too.

Biophysical Journal, 2002

We were very interested in the paper by on the modeling of the kinetic and equilibrium binding of myosin S1 to regulated actin filaments, containing actin, tropomyosin, and troponin (ATmTn). This is a formidable task, and the authors of the paper are to be commended on their considerable achievement. They have made a detailed comparison of the Hill et al. two-state model (1980) (referred to as the Hill model) and the McKillop and Geeves three-state model (1993) (referred to as the M and G model) and concluded that both can adequately describe the data. This could be interpreted, using Occam's razor, that a three-state model is not necessary. Although we would not wish to disagree with their calculations, we wish to point out that the authors: 1) have considered only some of the available data to test the two models; 2) have not compared the ability of the models to address fundamental issues in thin filament regulation; and 3) have not related the mathematical parameters of the models to the properties of the components.

Proteins-structure Function and Bioinformatics, 2002

Realistic studies of ion current in biologic channels present a major challenge for computer simulation approaches. All-atom molecular dynamics simulations involve serious time limitations that prevent their use in direct evaluation of ion current in channels with significant barriers. The alternative use of Brownian dynamics (BD) simulations can provide the current for simplified macroscopic models. However, the time needed for accurate calculations of electrostatic energies can make BD simulations of ion current expensive. The present work develops an approach that overcomes some of the above challenges and allows one to simulate ion currents in models of biologic channels. Our method provides a fast and reliable estimate of the energetics of the system by combining semimacroscopic calculations of the self-energy of each ion and an implicit treatment of the interactions between the ions, as well as the interactions between the ions and the protein-ionizable groups. This treatment involves the use of the semimacroscopic version of the protein dipole Langevin dipole (PDLD/S) model in its linear response approximation (LRA) implementation, which reduces the uncertainties about the value of the protein “dielectric constant.” The resulting free energy surface is used to generate the forces for on-the-fly BD simulations of the corresponding ion currents. Our model is examined in a preliminary simulation of the ion current in the KcsA potassium channel. The complete free energy profile for a single ion transport reflects reasonable energetics and captures the effect of the protein-ionized groups. This calculated profile indicates that we are dealing with the channel in its closed state. Reducing the barrier at the gate region allows us to simulate the ion current in a reasonable computational time. Several limiting cases are examined, including those that reproduce the observed current, and the nature of the productive trajectories is considered. The ability to simulate the current in realistic models of ion channels should provide a powerful tool for studies of the biologic function of such systems, including the analysis of the effect of mutations, pH, and electric potentials. Proteins 2002;47:265–280. © 2002 Wiley-Liss, Inc.

Soft Matter, 2005

The cell membrane, confining some ions and molecules on one side and exchanging others with the other side, is the ultimate unit of the physiology of life. The delicate task of regulating the transport of ions across the membrane is carried out by biological nanotubes called 'ion channels'. Recently, there have been enormous strides in our understanding of the structure-function relationships of biological ion channels. The molecular structures of several ion channels have been determined from crystallographic analysis, including potassium channels, mechanosensitive channels, a chloride channel, as well as gramicidin channels and porins. It is expected that the X-ray structures of other ion channels will soon follow these discoveries, ushering in a new era of ion channel studies in which predicting the function of channels from their atomic structures will become the main quest. In parallel to these experimental findings, there have been important advances in computational biophysics. Here we summarize three theoretical approaches that have been utilized to understand the dynamics of ion permeation across bio-nanotubes, highlighting their advantages and shortcomings, and briefly describe some of the salient properties of ion channels uncovered through computational studies.

2003

Experiments show that single stranded nucleic acids polymers can be transported across an alpha hemolysin channel under the action of an applied electric field. The translocation of the nucleic acid polymers causes transient blockades in the ion current. The physical and chemical details of the interactions between polymer, channel and ionic solution that lead to the blockade events are not yet fully understood. Atomistic simulations enable a realistic description of the dynamic motions of the solvated polymer-pore system as a function of time. Analysis of such calculated system trajectories leads to valuable insight possible energy barriers, ion mobilities and short time-scale interactions. This study investigates the relationship between the structural properties of the alpha hemolysin channel and the ionic current blockades that result from the translocation of single stranded nucleic acids.