Conformational changes of an ion-channel during gating and emerging electrophysiologic properties: Application of a computational approach to cardiac Kv7.1.

Ion channels are the "building blocks" of the excitation process in excitable tissues. Despite advances in determining their molecular structure, understanding the relationship between channel protein structure and electrical excitation remains a challenge. The Kv7.

Physically-induced cytoskeleton remodeling of cells in three-dimensional culture.

Characterizing how cells in three-dimensional (3D) environments or natural tissues respond to biophysical stimuli is a longstanding challenge in biology and tissue engineering. We demonstrate a strategy to monitor morphological and mechanical responses of contractile fibroblasts in a 3D environment. Cells responded to stretch through specific, cell-wide mechanisms involving staged retraction and reinforcement.

Quantification of fibre polymerization through Fourier space image analysis.

Quantification of changes in the total length of randomly oriented and possibly curved lines appearing in an image is a necessity in a wide variety of biological applications. Here, we present an automated approach based upon Fourier space analysis. Scaled, band-pass filtered power spectral densities of greyscale images are integrated to provide a quantitative measurement of the total length of lines of a particular range of thicknesses appearing in an image.

Continuum molecular simulation of large conformational changes during ion-channel gating.

A modeling framework was developed to simulate large and gradual conformational changes within a macromolecule (protein) when its low amplitude high frequency vibrations are not concerned. Governing equations were derived as alternative to Langevin and Smoluchowski equations and used to simulate gating conformational changes of the Kv7.1 ion-channel over the time scale of its gating process (tens of milliseconds).

Three-residue loop closure in proteins: a new kinematic method reveals a locus of connected loop conformations.

The closure of a three-residue loop was studied using a developed kinematic method. It was shown that there are infinite number of three-residue loops (a locus of conformations), which can connect two segments of a polypeptide. This adds to the current understanding of a finite number of conformations for three-residue loop-closure.

State-dependent electrostatic interactions of S4 arginines with E1 in S2 during Kv7.1 activation.

The voltage-sensing domain of voltage-gated channels is comprised of four transmembrane helices (S1-S4), with conserved positively charged residues in S4 moving across the membrane in response to changes in transmembrane voltage. Although it has been shown that positive charges in S4 interact with negative countercharges in S2 and S3 to facilitate protein maturation, how these electrostatic interactions participate in channel gating remains unclear. We studied a mutation in Kv7.

A multiscale model linking ion-channel molecular dynamics and electrostatics to the cardiac action potential.

Ion-channel function is determined by its gating movement. Yet, molecular dynamics and electrophysiological simulations were never combined to link molecular structure to function. We performed multiscale molecular dynamics and continuum electrostatics calculations to simulate a cardiac K(+) channel (I(Ks)) gating and its alteration by mutations that cause arrhythmias and sudden death.

Stretch-activated force shedding, force recovery, and cytoskeletal remodeling in contractile fibroblasts.

The stress fiber network within contractile fibroblasts structurally reinforces and provides tension, or "tone", to tissues such as those found in healing wounds. Stress fibers have previously been observed to polymerize in response to mechanical forces. We observed that, when stretched sufficiently, contractile fibroblasts diminished the mechanical tractions they exert on their environment through depolymerization of actin filaments then restored tissue tension and rebuilt actin stress fibers through staged Ca(++)-dependent processes.

Modeling subunit cooperativity in opening of tetrameric ion channels.

Most potassium channels are tetramers of four homologous polypeptides (subunits). During channel gating, each subunit undergoes several conformational changes independent of the state of other subunits before reaching a permissive state, from which the channel can open. However, transition from the permissive states to the open state involves a concerted movement of all subunits.

Statistical properties of ion channel records. Part II: estimation from the macroscopic current.

Macroscopic ion channel current is the summation of the stochastic records of individual channel currents and therefore relates to their statistical properties. As a consequence of this relationship, it may be possible to derive certain statistical properties of single channel records or even generate some estimates of the records themselves from the macroscopic current when the direct measurement of single channel currents is not applicable. We present a procedure for generating the single channel records of an ion channel from its macroscopic current when the stochastic process of channel gating has the following two properties: (I) the open duration is independent of the time of opening event and has a single exponential probability density function (pdf), (II) all the channels have the same probability to open at time t.

Statistical properties of ion channel records. Part I: relationship to the macroscopic current.

Macroscopic ion channel current can be derived by summation of the stochastic records of individual channel currents. In this paper, we present two probability density functions of single channel records that can uniquely determine the macroscopic current regardless of other statistical properties of records or the stochastic model of channel gating (presented often with stationary Markov models). We show that H(t), probability density function of channel opening events (introduced explicitly in this paper), and D(t), probability density function of the open duration (sometimes has named dwell time distribution as well), determine the normalized macroscopic current, G(t), through G(t) = P(t) - H(t) * Q(t) where P(t) is the cumulative density function of H(t), Q(t) is the cumulative density function of D(t), * is the symbol of convolution integral and G(t) is the macroscopic current divided by the amplitude of single channel current and the number of single channel sweeps.

A simplified approach to quasi-linear viscoelastic modeling.

The fitting of quasi-linear viscoelastic (QLV) constitutive models to material data often involves somewhat cumbersome numerical convolution. A new approach to treating quasi-linearity in 1-D is described and applied to characterize the behavior of reconstituted collagen. This approach is based on a new principle for including nonlinearity and requires considerably less computation than other comparable models for both model calibration and response prediction, especially for smoothly applied stretching.

Incremental mechanics of collagen gels: new experiments and a new viscoelastic model.

Paired incremental uniaxial step (i.e., relaxation) and ramp tests were conducted simultaneously on four (nominally) identical samples of type I collagen gel, over a direct strain range 0 < epsilon < 0.