Molecular dynamics simulations of ion channels formed by bundles of amphipathic α-helical peptides

Ion channels may be formed by self-assembly of amphipathic α-helical peptides into parallel helix bundles. The transbilayer pores formed by such peptides contain extended columns of water molecules, the properties of which may differ from those of water in its bulk state. The de novo designed peptides of DeGrado et al., which contain only leucine and serine residues, are considered as a simple example of such channels. Molecular dynamics simulations of peptide helix bundles with water molecules within and at the mouths of their pores are used to refine such models and to investigate the properties of intra-pore water. The translational and rotational mobility of water molecules within the pores are reduced relative to bulk water. Furthermore, intra-pore waters orient themselves with their dipoles anti-parallel to the helix dipoles, as do the hydroxyl groups of serine residues. Comparison of approximate predictions of ionic conductances with experimental values provides support for the validity of these models. Received: 23 April 1996 / Accepted: 7 August 1996     

Reservoir boundaries in Brownian dynamics simulations of ion channels

Brownian dynamics (BD) simulations provide a practical method for the calculation of ion channel conductance from a given structure. There has been much debate about the implementation of reservoir boundaries in BD simulations in recent years, with claims that the use of improper boundaries could have large effects on the calculated conductance values. Here we compare the simple stochastic boundary that we have been using in our BD simulations with the recently proposed grand canonical Monte Carlo method. We also compare different methods of creating transmembrane potentials. Our results confirm that the treatment of the reservoir boundaries is mostly irrelevant to the conductance properties of an ion channel as long as the reservoirs are large enough.     

Molecular dynamics simulations of ion distribution in nanochannels

Molecular dynamics simulations of ion distribution in a nanochannel were performed using a three region simulation domain including two bulk regions on each side of the nanochannel. This scheme allows the study of ion concentration and distribution inside the nanochannel under a given bulk electrolyte concentration, i.e. when the molecular system reaches equilibrium, the concentrations of the counter- and co-ions inside the nanochannel corresponding to a bulk electrolyte will emerge naturally. Our approach is in sharp contrast to the common practice in modeling electric double layers where the number of ions in the nanochannel is assigned somewhat arbitrarily, corresponding to an unknown bulk concentration.     

Molecular dynamics simulations reveal highly permeable oxygen exit channels shared with water uptake channels in photosystem II

Photosystem II (PSII) catalyzes the oxidation of water in the conversion of light energy into chemical energy in photosynthesis. Water delivery and oxygen removal from the oxygen evolving complex (OEC), buried deep within PSII, are critical requirements to facilitate the reaction and minimize reactive oxygen damage. It has often been assumed that water and oxygen travel through separate channels within PSII, as demonstrated in cytochrome c oxidase. This study describes all-atom molecular dynamics simulations of PSII designed to investigate channels by fully characterizing the distribution and permeation of both water and oxygen. Interestingly, most channels found in PSII were permeable to both oxygen and water, however individual channels exhibited different energetic barriers for the two solutes. Several routes for oxygen diffusion within PSII with low energy permeation barriers were found, ensuring its fast removal from the OEC. In contrast, all routes for water showed significant energy barriers, corresponding to a much slower permeation rate for water through PSII. Two major factors were responsible for this selectivity: (1) hydrogen bonds between water and channel amino acids, and (2) steric restraints. Our results reveal the presence of a shared network of channels in PSII optimized to both facilitate the quick removal of oxygen and effectively restrict the water supply to the OEC to help stabilize and protect it from small water soluble inhibitors.     

Molecular dynamics simulations of ion separation in nano-channel water flows using an electric field

ABSTRACT

Removal of undesired substances from water is a field of investigation recently focused at the nanoscale. Towards this direction, molecular dynamics simulations are conducted in this paper to investigate unwanted ion removal in nanochannel flows. The simulation method incorporates a Poiseuille-like water/ion flow system at the nanoscale where an electric field, of various magnitudes in the range of E?=?0.25–1.5?V/Å, is applied perpendicular to the flow, leading anions and cations close to the wall regions, similar to the Capacitive De-Ionization method. The time needed for ions to reach equilibrium, i.e. to flow in the region near the walls while pure water flows in the channel interior, is t?=?1.3?ns when E?=?1.5?V/Å and t?=?4.0?ns when E?=?0.25?V/Å, showing a dependency on the value of the electric field. Calculations on density, velocity, and temperature values report on fluid properties to be used in the proposed desalination configuration and could act as a basis to guide novel technological applications and extend to higher scales.     

Molecular dynamics simulations of Leu-enkephalin in water and DMSO.

The structure of Leu-enkephalin (L-Enk) and Met-enkephalin (M-Enk) have frequently been studied, in particular by nuclear magnetic resonance spectroscopy. After more than 20 years of research, it was concluded that enkephalins have no preferred structure in aqueous solution, but that they may have in other solvents. We have performed molecular dynamics simulations of zwitterionic L-Enk in water, and zwitterionic as well as neutral L-Enk dimethyl sulfoxide (DMSO). In water the peptide is very flexible, although there seems to be a preference for compact conformations. In DMSO, the peptide forms a clear salt bridge in the zwitterionic form, but has no preferred conformation in the neutral form. This difference in conformation may provide an explanation for measurements in DMSO in which multiple conformations were found to exist. In this paper we introduce a new formulation for a dihedral angle autocorrelation function, and apply it to study side-chain dynamics in L-Enk. We find that the side-chain dynamics of the large Tyr and Phe residues cannot be adequately sampled in 2.0-ns simulations, while this does seem to be possible for the smaller Leu side chain.     

Molecular dynamics simulations of isolated transmembrane helices of potassium channels

In the middle of the S6 helix in voltage-gated potassium channels there is a highly conserved Pro-Val-Pro motif, while the equivalent M2 helix of inward rectifier potassium channels contains a conserved glycine residue in a comparable position. The structural implications of these conserved motifs are of interest given the evidence that S6 and M2 are components of the lining of their respective pores. Multiple sequence alignment and TM helix prediction methods were used to define consensus regions for S6 and M2. Ensembles of 50 structures for each helix were generated by simulated annealing and restrained molecular dynamics. Time-dependent fluctuations of S6 and M2 were investigated by long time scale molecular dynamics simulations on representative members of each ensemble carried out in vacuo in the presence and absence of a hydrophobic potential that mimics a lipid bilayer. The results are discussed in terms of the structural basis of the kink in S6 and M2 and of a putative functional role for flexible helices as “molecular swivels.” © 1996 John Wiley & Sons, Inc.     

Molecular dynamics study of ion transport in transmembrane protein channels

Ion transport through biological membranes often takes place via pore-like protein channels. The elementary process of this transport can be described as a motion of the ion in a quasi-periodic multi-well potential. In this study molecular dynamics simulations of ion transport in a model channel were performed in order to test the validity of reaction-rate theory for this process. The channel is modelled as a hexagonal helix of infinite length, and the ligand groups interacting with the ion are represented by dipoles lining the central hole of the channel. The dipoles interact electrostatically with each other and are allowed to oscillate around an equilibrium orientation. The coupled equations of motion for the ion and the dipoles were solved simultaneously with the aid of a numerical integration procedure. From the calculated ion trajectories it is seen that, particularly at low temperatures, the ion oscillates back and forth in the trapping site many times before it leaves the site and jumps over the barrier. The observed oscillation frequency was found to be virtually temperature-independent (nu 0 approximately equal to 2 X 10(12) s-1) so that the strong increase of transport rate with temperature results almost exclusively from the Arrhenius-type exponential dependence of jump probability w on 1/T. At higher temperatures simultaneous jumps over several barriers occasionally occur. Although the exponential form of w(T) was in agreement with the predictions of rate theory, the activation energy Ea as determined from w(T) was different from the barrier height which was calculated from the static potential of the ion in the channel; the actual transport rate was 1 X 10(3) times higher than the rate predicted from the calculated barrier height. This observation was interpreted by the notion that ion transport in the channel is strongly influenced by thermal fluctuations in the conformation of the ligand system which in turn give rise to fluctuations of barrier height.     

Molecular dynamics simulations

Molecular dynamics simulations have become a standard tool for the investigation of biomolecules. Simulations are performed of ever bigger systems using more realistic boundary conditions and better sampling due to longer sampling times. Recently, realistic simulations of systems as complex as transmembrane channels have become feasible. Simulations aid our understanding of biochemical processes and give a dynamic dimension to structural data; for example, the transformation of harmless prion protein into the disease-causing agent has been modeled.     

Semi-Markov models for brownian dynamics permeation in biological ion channels

Constructing accurate computational models that explain how ions permeate through a biological ion channel is an important problem in biophysics and drug design. Brownian dynamics simulations are large-scale interacting particle computer simulations for modeling ion channel permeation but can be computationally prohibitive. In this paper, we show the somewhat surprising result that a small-dimensional semi-Markov model can generate events (such as conduction events and dwell times at binding sites in the protein) that are statistically indistinguishable from brownian dynamics computer simulation. This approach enables the use of extrapolation techniques to predict channel conduction when performing the actual brownian dynamics simulation that is computationally intractable. Numerical studies on the simulation of gramicidin A ion channels are presented.     

Simulation of molecular dynamics of water movement in ion channels

The motion of water molecules in a gramicidin-like channel was studied by the molecular dynamics method. Water molecules are presented in the ST2 model. The structure of the channel was presented in the form of channel's helix frame possessing mobile dipole groups. The interaction of all mobile particles with the membrane channel's walls was taken into account. The calculation consisted of 50,000 integration steps of delta t = 5 x 10(-16) s which corresponded to a total elapsed time of 25 ps. It was shown that water molecules in the channel did not possess rigid spatial structure but exhibited a structure oriented along the channel axis. The motion of water molecules in the channel occurred smoothly, i.e. all water molecules did not have any deep, stable potential wells in the channel. The distribution of water molecules along the radial coordinate of the channel was estimated. Water density was shown to be maximal near the channel axis.     

Molecular mechanics and dynamics simulations of various dispersant models on the water surface (001)

Five dispersant-molecule models of succinimide, acrylate, imide, phenylsulfonic and salicyl were used to study their interactions with the water surface (001). The interaction energy, molecular configuration, charge distribution and radial distribution function (RDF) curve for each of the dispersant molecules were analyzed from the molecular mechanics (MM) and molecular dynamics (MD) simulation results. It can be seen that the system energies, mostly electrostatic and hydrogen bond energies, were reduced significantly when the dispersant molecules interacted with the water surface. The hydrophilic group of a dispersant molecule can attach itself to the water surface firmly and reach for a stable energy-minimized configuration, which is helpful to the dispersants' dispersancy. The influence exerted by the hydrophobic group of the dispersant molecule, which was the substituted hydrocarbon chain of n-octadecanyl in this paper, is discussed in comparison with the naked polar headgroup. Steric configuration, charge distribution and substitute hydrocarbon chain of the dispersant molecule influenced the interaction between dispersants and polar water surface.     

Molecular dynamics simulations of helix denaturation.

An understanding of the structural transitions that an alpha-helix undergoes will help to elucidate such motions in proteins and their role in protein folding. We present the results of molecular dynamics simulations to investigate these transitions in a short polyalanine peptide (13 residues) both in vacuo and in the presence of solvent. The denaturation of this peptide was monitored as a function of temperature (ranging from 5 to 200 degrees C). In vacuo, the helical state predominated at all temperatures, whereas in solution the helix melted with increasing temperature. The peptide was predominantly helical at low temperature in solution, while at intermediate temperatures the peptide spent the bulk of the time fluctuating between different conformations with intermediate amounts of helix, e.g. not completely helical nor entirely non-helical. Many of these conformations consisted of short helical segments with intervening non-helical residues. At high temperature the peptide unfolded and adopted various collapsed unstructured states. The intrahelical hydrogen bonds that break at high temperature were not fully compensated by hydrogen bonds with water molecules in the partially unfolded forms of the peptide. Increases in temperature disrupted both the helical structure and the peptide-water interactions. Water played a major but indirect role in facilitating unfolding, as opposed to specifically competing for the intrapeptide hydrogen bonds. The implications of our results to protein folding are discussed.     

Molecular dynamics simulations of interaction between sub-bituminous coal and water

The high moisture content of sub-bituminous coal is associated with the interactions between coal and water. Because of complex composition and structure, the graphite surface modified by hydroxyl, carboxyl and carbonyl groups was used to represent the surface model of sub-bituminous coal according to XPS results. Density profiles for oxygen atoms and hydrogen atoms indicate that the coal surface properties affect the structural and dynamic characteristics of the interfacial water molecules. The interfacial water exhibits much more ordering than bulk water. The results of radial distribution functions, mean square displacement and local self-diffusion coefficient for water molecule related to three oxygen moieties confirmed that the water molecules prefer to absorb with carboxylic groups, and adsorption of water molecules at the hydroxy and carbonyl is similar.     

Molecular dynamics of synthetic leucine-serine ion channels in a phospholipid membrane

Molecular dynamics calculations were carried out on models of two synthetic leucine-serine ion channels: a tetrameric bundle with sequence (LSLLLSL)(3)NH(2) and a hexameric bundle with sequence (LSSLLSL)(3)NH(2). Each protein bundle is inserted in a palmitoyloleoylphosphatidylcholine bilayer membrane and solvated by simple point charge water molecules inside the pore and at both mouths. Both systems appear to be stable in the absence of an electric field during the 4 ns of molecular dynamics simulation. The water motion in the narrow pore of the four-helix bundle is highly restricted and may provide suitable conditions for proton transfer via a water wire mechanism. In the wider hexameric pore, the water diffuses much more slowly than in bulk but is still mobile. This, along with the dimensions of the pore, supports the observation that this peptide is selective for monovalent cations. Reasonable agreement of predicted conductances with experimentally determined values lends support to the validity of the simulations.     

Symmetry‐restrained molecular dynamics simulations improve homology models of potassium channels

Most crystallized homo‐oligomeric ion channels are highly symmetric, which dramatically decreases conformational space and facilitates building homology models (HMs). However, in molecular dynamics (MD) simulations channels deviate from ideal symmetry and accumulate thermal defects, which complicate the refinement of HMs using MD. In this work we evaluate the ability of symmetry constrained MD simulations to improve HMs accuracy, using an approach conceptually similar to Critical Assessment of techniques for protein Structure Prediction (CASP) competition: build HMs of channels with known structure and evaluate the efficiency of proposed methods in improving HMs accuracy (measured as deviation from experimental structure). Results indicate that unrestrained MD does not improve the accuracy of HMs, instantaneous symmetrization improves accuracy but not stability of HMs during subsequent unrestrained MD, while gradually imposing symmetry constraints improves both accuracy (by 5–50%) and stability of HMs. Moreover, accuracy and stability are strongly correlated, making stability a reliable criterion in predicting the accuracy of new HMs. Proteins 2010. © 2009 Wiley‐Liss, Inc.