Microtubules are significant therapeutic targets for the treatment of cancer, where suppression of microtubule dynamicity by drugs such as paclitaxel forms the basis of clinical efficacy. Peloruside A, a macrolide isolated from New Zealand marine sponge Mycale hentscheli, is a microtubule-stabilizing agent that synergizes with taxoid drugs through a unique site and is an attractive lead compound in the development of combination therapies. We report here unique allosteric properties of microtubule stabilization via peloruside A and present a structural model of the peloruside-binding site. Using a strategy involving comparative hydrogen-deuterium exchange mass spectrometry of different microtubule-stabilizing agents, we suggest that taxoid-site ligands epothilone A and docetaxel stabilize microtubules primarily through improved longitudinal interactions centered on the interdimer interface, with no observable contributions from lateral interactions between protofilaments. The mode by which peloruside A achieves microtubule stabilization also involves the interdimer interface, but includes contributions from the alpha/beta-tubulin intradimer interface and protofilament contacts, both in the form of destabilizations. Using data-directed molecular docking simulations, we propose that peloruside A binds within a pocket on the exterior of beta-tubulin at a previously unknown ligand site, rather than on alpha-tubulin as suggested in earlier studies.
RASSF1A is a tumor suppressor protein involved in death receptor-dependent apoptosis utilizing the Bax-interacting protein MOAP-1 (previously referred to as MAP-1). However, the dynamics of death receptor recruitment of RASSF1A and MOAP-1 are still not understood. We have now detailed recruitment to death receptors (tumor necrosis factor receptor 1 [TNF-R1] and TRAIL-R1/DR4) and identified domains of RASSF1A and MOAP-1 that are required for death receptor interaction. Upon TNF-␣ stimulation, the C-terminal region of MOAP-1 associated with the death domain of TNF-R1; subsequently, RASSF1A was recruited to MOAP-1/TNF-R1 complexes. Prior to recruitment to TNF-R1/MOAP-1 complexes, RASSF1A homodimerization was lost. RASSF1A associated with the TNF-R1/MOAP-1 or TRAIL-R1/MOAP-1 complex via its N-terminal cysteine-rich (C1) domain containing a potential zinc finger binding motif. Importantly, TNF-R1 association domains on both MOAP-1 and RASSF1A were essential for death receptor-dependent apoptosis. The association of RASSF1A and MOAP-1 with death receptors involves an ordered recruitment to receptor complexes to promote cell death and inhibit tumor formation.
We present a new methodology for computing solvation free energy, which is based upon the reference interaction site model (RISM)/hypernetted chain (HNC) solvation free energy expression, but which substitutes radial distribution functions taken from simulations for those calculated by simultaneous solution of the RISM and HNC equations. Consequently, solvation free energy can be obtained from a single molecular dynamics or Monte Carlo simulation. Here we describe in detail the coupled RISM/simulation approach, and offer some error analysis. Finally we give the results of its application to a set of small test molecules in aqueous solution. The success shown in some of our results demonstrates that the coupled RISM/simulation approach is worth considering further as a potentially useful tool in studies of solvated systems, such as aqueous molecular biosystems.
The cytoskeleton is essential to cell morphology, cargo trafficking, and cell division. As the neuronal cytoskeleton is extremely complex, it is no wonder that a startling number of neurodegenerative disorders (including but not limited to Alzheimer’s disease, Parkinson’s disease and Huntington’s disease) share the common feature of a dysfunctional neuronal cytoskeleton. Recently, concern has been raised about a possible link between anesthesia, post-operative cognitive dysfunction, and the exacerbation of neurodegenerative disorders. Experimental investigations suggest that anesthetics bind to and affect cytoskeletal microtubules, and that anesthesia-related cognitive dysfunction involves microtubule instability, hyper-phosphorylation of the microtubule-associated protein tau, and tau separation from microtubules. However, exact mechanisms are yet to be identified. In this paper the interaction of anesthetics with the microtubule subunit protein tubulin is investigated using computer-modeling methods. Homology modeling, molecular dynamics simulations and surface geometry techniques were used to determine putative binding sites for volatile anesthetics on tubulin. This was followed by free energy based docking calculations for halothane (2-bromo-2-chloro-1,1,1-trifluoroethane) on the tubulin body, and C-terminal regions for specific tubulin isotypes. Locations of the putative binding sites, halothane binding energies and the relation to cytoskeleton function are reported in this paper.
Memristors represent the fourth electrical circuit element complementing resistors, capacitors and inductors. Hallmarks of memristive behavior include pinched and frequency-dependent I-V hysteresis loops and most importantly a functional dependence of the magnetic flux passing through an ideal memristor on its electrical charge. Microtubules (MTs), cylindrical protein polymers composed of tubulin dimers are key components of the cytoskeleton. They have been shown to increase solution's ionic conductance and re-orient in the presence of electric fields. It has been hypothesized that MTs also possess intrinsic capacitive and inductive properties, leading to transistor-like behavior. Here, we show a theoretical basis and experimental support for the assertion that MTs under specific circumstances behave consistently with the definition of a memristor. Their biophysical properties lead to pinched hysteretic current-voltage dependence as well a classic dependence of magnetic flux on electric charge. Based on the information about the structure of MTs we provide an estimate of their memristance. We discuss its significance for biology, especially neuroscience, and potential for nanotechnology applications. MemristorsThe term memristor is the contraction of memory and resistor and it was first proposed in 1971 as the fourth element of the electric circuits 1 . A memristor is defined as a two-terminal passive circuit element that provides a functional relation between electric charge and magnetic flux 1,2 . The first physical realization of a memristor was achieved in 2008 2,3 and it has held a promise of nanoelectronics beyond Moore's law 4 , although this realization has been both difficult and controversial 5 . One of the possible breakthrough applications of memristors is neuromorphic computing 6 . Memristance refers to a property of the memristor that is analogous to resistance but it also depends on the history of applied voltage or injected current, unlike in other electrical circuit elements. When the electrical charge flows in one direction, the resistance of some memristors increases while it decreases when the charge flows in the opposite direction or vice versa. If the applied voltage is turned off, the memristor retains the last resistance value that it exhibited. This history dependence of memristance is expressed via a self-crossing or pinched I-V loop, which is frequency dependent 3,6 , and whose lobe area tends to zero as the frequency tends to infinity.A memristor is said to be charge-controlled if the relation between flux ϕ and charge q is: ϕ = ϕ (q). Conversely, it is said to be flux-controlled if q = q(ϕ). The voltage v of a charge-controlled memristor obeys a linear relationship with the current i(t) representing a charge-dependent Ohm's law such that: v(t) M(q) i(t)(1) = where memristance is defined as:
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