scholarly journals Conformational exchange in the potassium channel blocker ShK

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Naoto Iwakawa ◽  
Nicola J. Baxter ◽  
Dorothy C. C. Wai ◽  
Nicholas J. Fowler ◽  
Rodrigo A. V. Morales ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Chemical Shift ◽  
Structural Changes ◽  
Channel Blocker ◽  
Active Form ◽  
Conformational Exchange ◽  
Solvent Exposure ◽  
Alternative State ◽  
Phase 1B ◽  
Dynamics Simulations

AbstractShK is a 35-residue disulfide-linked polypeptide produced by the sea anemone Stichodactyla helianthus, which blocks the potassium channels Kv1.1 and Kv1.3 with pM affinity. An analogue of ShK has been developed that blocks Kv1.3 > 100 times more potently than Kv1.1, and has completed Phase 1b clinical trials for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis. Previous studies have indicated that ShK undergoes a conformational exchange that is critical to its function, but this has proved difficult to characterise. Here, we have used high hydrostatic pressure as a tool to increase the population of the alternative state, which is likely to resemble the active form that binds to the Kv1.3 channel. By following changes in chemical shift with pressure, we have derived the chemical shift values of the low- and high-pressure states, and thus characterised the locations of structural changes. The main difference is in the conformation of the Cys17-Cys32 disulfide, which is likely to affect the positions of the critical Lys22-Tyr23 pair by twisting the 21–24 helix and increasing the solvent exposure of the Lys22 sidechain, as indicated by molecular dynamics simulations.

Tuning the Electric Field Response of MOFs by Rotatable Dipolar Linkers

2019 ◽  
Author(s):  
Johannes P. Dürholt ◽  
Babak Farhadi Jahromi ◽  
Rochus Schmid
Keyword(s):  
Electric Field ◽  
Electric Fields ◽  
Structural Changes ◽  
Dielectric Behavior ◽  
Two Dimensions ◽  
Dielectric Constants ◽  
Electric Response ◽  
Dipole Strength ◽  
Metal Organic ◽  
Dynamics Simulations

Recently the possibility of using electric fields as a further stimulus to trigger structural changes in metal-organic frameworks (MOFs) has been investigated. In general, rotatable groups or other types of mechanical motion can be driven by electric fields. In this study we demonstrate how the electric response of MOFs can be tuned by adding rotatable dipolar linkers, generating a material that exhibits paralectric behavior in two dimensions and dielectric behavior in one dimension. The suitability of four different methods to compute the relative permittivity κ by means of molecular dynamics simulations was validated. The dependency of the permittivity on temperature T and dipole strength μ was determined. It was found that the herein investigated systems exhibit a high degree of tunability and substantially larger dielectric constants as expected for MOFs in general. The temperature dependency of κ obeys the Curie-Weiss law. In addition, the influence of dipolar linkers on the electric field induced breathing behavior was investigated. With increasing dipole moment, lower field strength are required to trigger the contraction. These investigations set the stage for an application of such systems as dielectric sensors, order-disorder ferroelectrics or any scenario where movable dipolar fragments respond to external electric fields.

scholarly journals Cofilin is a pH sensor for actin free barbed end formation: role of phosphoinositide binding

2008 ◽  
Vol 183 (5) ◽  
pp. 865-879 ◽  
Author(s):  
Christian Frantz ◽  
Gabriela Barreiro ◽  
Laura Dominguez ◽  
Xiaoming Chen ◽  
Robert Eddy ◽  
...  
Keyword(s):  
Actin Filament ◽  
Structural Changes ◽  
Ph Sensor ◽  
Ph Sensitive ◽  
Actin Binding ◽  
Filamentous Actin ◽  
Filament Dynamics ◽  
Ph Dependent ◽  
Dynamics Simulations

Newly generated actin free barbed ends at the front of motile cells provide sites for actin filament assembly driving membrane protrusion. Growth factors induce a rapid biphasic increase in actin free barbed ends, and we found both phases absent in fibroblasts lacking H+ efflux by the Na-H exchanger NHE1. The first phase is restored by expression of mutant cofilin-H133A but not unphosphorylated cofilin-S3A. Constant pH molecular dynamics simulations and nuclear magnetic resonance (NMR) reveal pH-sensitive structural changes in the cofilin C-terminal filamentous actin binding site dependent on His133. However, cofilin-H133A retains pH-sensitive changes in NMR spectra and severing activity in vitro, which suggests that it has a more complex behavior in cells. Cofilin activity is inhibited by phosphoinositide binding, and we found that phosphoinositide binding is pH-dependent for wild-type cofilin, with decreased binding at a higher pH. In contrast, phosphoinositide binding by cofilin-H133A is attenuated and pH insensitive. These data suggest a molecular mechanism whereby cofilin acts as a pH sensor to mediate a pH-dependent actin filament dynamics.

scholarly journals Effects of temperatures on pressure-induced structural changes in amorphous Si: A molecular-dynamics study

10.29007/6kp3 ◽  
2020 ◽  
Author(s):  
Renji Mukuno ◽  
Manabu Ishimaru
Keyword(s):  
Molecular Dynamics ◽  
Phase Transformation ◽  
Amorphous Phase ◽  
Structural Changes ◽  
Interatomic Potential ◽  
Activation Barrier ◽  
Distribution Functions ◽  
High Density ◽  
Angle Distribution ◽  
Dynamics Simulations

The structural changes of amorphous silicon (a-Si) under compressive pressure were examined by molecular-dynamics simulations using the Tersoff interatomic potential. a-Si prepared by melt-quenching methods was pressurized up to 30 GPa under different temperatures (300K and 500K). The density of a-Si increased from 2.26 to 3.24 g/cm3 with pressure, suggesting the occurrence of the low-density to high-density amorphous phase transformation. This phase transformation occurred at the lower pressure with increasing the temperature because the activation barrier for amorphous-to-amorphous phase transformation could be exceeded by thermal energy. The coordination number increased with pressure and time, and it was saturated at different values depending on the pressure. This suggested the existence of different metastable atomic configurations in a-Si. Atomic pair-distribution functions and bond-angle distribution functions suggested that the short-range ordered structure of high-density a-Si is similar to the structure of the high-pressure phase of crystalline Si (β-tin and Imma structures).

scholarly journals An instrumented sample holder for time-lapse microtomography measurements of snow under advective airflow

2014 ◽  
Vol 3 (2) ◽  
pp. 179-185 ◽  
Author(s):  
P. P. Ebner ◽  
S. A. Grimm ◽  
M. Schneebeli ◽  
A. Steinfeld
Keyword(s):  
Structural Changes ◽  
Time Lapse ◽  
Temperature Gradients ◽  
Sample Holder ◽  
Experimental Characterization ◽  
Computational Fluid Dynamics Simulations ◽  
Dynamics Simulations ◽  
Snow Samples

Abstract. An instrumented sample holder was developed for time-lapse microtomography of snow samples to enable in situ nondestructive spatial and temporal measurements under controlled advective airflows, temperature gradients, and air humidities. The design was aided by computational fluid dynamics simulations to evaluate the airflow uniformity across the snow sample. Morphological and mass transport properties were evaluated during a 4-day test run. This instrument allows the experimental characterization of metamorphism of snow undergoing structural changes with time.

scholarly journals DNA tension-modulated translocation and loop extrusion by SMC complexes revealed by molecular dynamics simulations

2021 ◽  
Author(s):  
Stefanos S Nomidis ◽  
Enrico Carlon ◽  
Stephan Gruber ◽  
John F Marko
Keyword(s):  
Molecular Dynamics ◽  
Structural Changes ◽  
Protein Complexes ◽  
Power Stroke ◽  
End Points ◽  
Domains Of Life ◽  
Dynamics Simulations ◽  
Fixed End ◽  
Atp Binding And Hydrolysis ◽  
Low Tension

Structural Maintenance of Chromosomes (SMC) protein complexes play essential roles in genome folding and organization across all domains of life. In order to determine how the activities of these large (about 50 nm) complexes are controlled by ATP binding and hydrolysis, we have developed a molecular dynamics (MD) model that realistically accounts for thermal conformational motions of SMC and DNA. The model SMCs make use of DNA flexibility and looping, together with an ATP-induced "power stroke", to capture and transport DNA segments, so as to robustly translocate along DNA. This process is sensitive to DNA tension: at low tension (about 0.1 pN), the model performs steps of roughly 60 nm size, while, at higher tension, a distinct inchworm-like translocation mode appears, with steps that depend on SMC arm flexibility. By permanently tethering DNA to an experimentally-observed additional binding site ("safety belt"), the same model performs loop extrusion. We find that the dependence of loop extrusion on DNA tension is remarkably different when DNA tension is fixed vs when DNA end points are fixed: Loop extrusion reversal occurs above 0.5 pN for fixed tension, while loop extrusion stalling without reversal occurs at about 2 pN for fixed end points. Our model quantitatively matches recent experimental results on condensin and cohesin, and makes a number of clear predictions. Finally we investigate how specific structural changes affect the SMC function, which is testable in experiments on varied or mutant SMCs.

scholarly journals All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery

2021 ◽  
Author(s):  
Carolina Pérez Segura ◽  
Boon Chong Goh ◽  
Jodi A. Hadden-Perilla
Keyword(s):  
Small Molecules ◽  
Drug Target ◽  
Structural Changes ◽  
Salt Bridge ◽  
Md Simulations ◽  
Health Concern ◽  
Protein Dimer ◽  
B Virus ◽  
Flexible Protein ◽  
Dynamics Simulations

AbstractThe hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important anti-viral paradigm based on disrupting the timing of genome encapsulation. Crystallographic studies of AT130-bound complexes have been essential in explaining the effects of the small molecule on HBV capsid structure; however, computational examination reveals that key changes attributed to AT130 were erroneous, likely a consequence of interpreting poor resolution arising from a highly flexible protein. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that, rather than damaging spike helicity, AT130 enhances the capsid’s ability to recover it. A new conformational state is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these domains. Combined with dynamical network analysis, results describe a connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire capsid protein dimer.

scholarly journals Structural variability and concerted motions of the T cell receptor – CD3 complex

2021 ◽  
Author(s):  
Prithvi R. Pandey ◽  
Bartosz Różycki ◽  
Reinhard Lipowsky ◽  
Thomas R. Weikl
Keyword(s):  
Molecular Dynamics ◽  
T Cell ◽  
Molecular Dynamics Simulations ◽  
T Cell Receptor ◽  
Tilt Angle ◽  
Structural Changes ◽  
Cell Receptor ◽  
Transmembrane Helices ◽  
Dynamics Simulations ◽  
Tcr Activation

AbstractWe investigate the structural and orientational variability of the membrane-embedded T cell receptor (TCR) – CD3 complex in extensive atomistic molecular dynamics simulations based on the recent cryo-EM structure determined by Dong et al. (2019). We find that the TCR extracellular (EC) domain is highly variable in its orientation by attaining tilt angles relative to the membrane normal that range from 15° to 55°. The tilt angle of the TCR EC domain is both coupled to a rotation of the domain and to characteristic changes throughout the TCR – CD3 complex, in particular in the EC interactions of the Cβ FG loop of the TCR, as well as in the orientation of transmembrane helices. The concerted motions of the membrane-embedded TCR – CD3 complex revealed in our simulations provide atomistic insights for force-based models of TCR activation, which involve such structural changes in response to tilt-inducing forces on antigen-bound TCRs.

scholarly journals Origin of the enhanced structural and reorientational relaxation rates in the presence of relatively weak dc electric fields

2004 ◽  
Vol 76 (1) ◽  
pp. 215-221 ◽  
Author(s):  
A. Vegiri
Keyword(s):  
Molecular Dynamics ◽  
Electric Field ◽  
Electric Fields ◽  
Structural Relaxation ◽  
Structural Changes ◽  
Common Mechanism ◽  
Weak Electric Field ◽  
Water Molecules ◽  
Relaxation Rates ◽  
Dynamics Simulations

The origin of the dramatic increase of the reorientational and structural relaxation rates of single water molecules in clusters of size N = 16, 32, and 64 at T = 200 K, under the influence of an external, relatively weak electric field (~0.5 107 V/cm) is examined through molecular dynamics simulations. The observed effect is attributed not to any profound structural changes, but to the increase of the size of the molecular cage. The response of water to an electric field in this range shows many similarities with the dynamics of water under low pressure. By referring to simulations and experiments from the literature, we show that in both cases the observed effects are dictated by a common mechanism.

Sign in / Sign up

Export Citation Format

Share Document