MSM/RD: Coupling Markov state models of molecular kinetics with reaction-diffusion simulations

Molecular dynamics (MD) simulations can model the interactions between macromolecules with high spatiotemporal resolution but at a high computational cost. By combining high-throughput MD with Markov state models (MSMs), it is now possible to obtain long-timescale behavior of small to intermediate biomolecules and complexes. To model the interactions of many molecules at large lengthscales, particle-based reaction-diffusion (RD) simulations are more suitable but lack molecular detail. Thus, coupling MSMs and RD simulations (MSM/RD) would be highly desirable, as they could efficiently produce simulations at large time- and lengthscales, while still conserving the characteristic features of the interactions observed at atomic detail. While such a coupling seems straightforward, fundamental questions are still open: Which definition of MSM states is suitable? Which protocol to merge and split RD particles in an association/dissociation reaction will conserve the correct bimolecular kinetics and thermodynamics? In this paper, we make the first step towards MSM/RD by laying out a general theory of coupling and proposing a first implementation for association/dissociation of a protein with a small ligand (A + B C). Applications on a toy model and CO diffusion into the heme cavity of myoglobin are reported

Abordagem nutrológica do transtorno do déficit de atenção e hiperatividade em crianças

The aim of this study was to conduct a non-systematic literature review on the nutrological approach to the Attention Deficit Hyperactivity Disorder (ADHD) in children. The numerous nutrological treatments that have been proposed include restriction and elimination diets (REDs), supplementation with omega-3 fatty acids, iron, zinc and magnesium

Description of Litomosoides ysoguazu n. sp. (Nematoda, Onchocercidae), a parasite of the tuft-toed rice rat Sooretamys angouya (Fischer) (Rodentia: Cricetidae), and a first record of L. esslingeri Bain, Petit & Berteaux, 1989 in Paraguay

Paraguay is a small landlocked country whose mammalian fauna is among the least studied in South America, as well as their parasites. As a result of a study of the effects of habitat fragmentation on small mammal biodiversity in eastern Paraguay, we have collected some parasites of cricetid rodents. Herein, we describe a new species of Litomosoides Chandler, 1931 parasitising the body cavity of the tuft-toed rice rat Sooretamys angouya (Fischer) and Litomosoides esslingeri Bain, Petit & Diagne, 1989 parasitising Oligoryzomys nigripes (Olfers), thus expanding its geographical distribution into Paraguay. Litomosoides ysoguazu n. sp. is characterised by the large size of the females (92.2–117.6 mm long) and by having buccal capsule with an anterior widening with rounded edges on the chitinous segment and a rounded widening at the base; male tail with a single pair of adcloacal papillae, three to five pairs of asymmetrical postcloacal papillae, and one or two unpaired papillae in the median ventral line; spicules corresponding to the “sigmodontis” species group; and microfilaria with a sheath stuck to the body and visible in the anterior extremity. We also describe a fourth-stage female larva. Oligoryzomys nigripes is a new host record of L. esslingeri; this enlarges the host record to eight species highlighting the low specificity of this species.Facultad de Ciencias Naturales y Muse

Surface tension of the Widom-Rowlinson model

11 pags., 5 figs., 3 tabs.We consider the computation of the surface tension of the fluid-fluid interface for the Widom-Rowlinson [J. Chem. Phys. 52, 1670 (1970)] binary mixture from direct simulation of the inhomogeneous system. We make use of the standard mechanical route, in which the surface tension follows from the computation of the normal and tangential components of the pressure tensor of the system. In addition to the usual approach, which involves simulations of the inhomogeneous system in the canonical ensemble, we also consider the computation of the surface tension in an ensemble where the pressure perpendicular (normal) to the planar interface is kept fixed. Both approaches are seen to provide consistent values of the interfacial tension. The issue of the system-size dependence of the surface tension is addressed. In addition, simulations of the fluid-fluid coexistence properties of the mixture are performed in the semigrand canonical ensemble. Our results are compared with existing data of the Widom-Rowlinson mixture and are also examined in the light of the vapor-liquid equilibrium of the thermodynamically equivalent one-component penetrable sphere model. © 2007 American Institute of Physics.Financial support is due to the Spanish Dirección General de Investigación Project Nos. FIS2004-06627-C02-01 E.d.M. and FIS2004-02954-C03-01 N.G.A. and from Universidad de Huelva and Junta de Andalucía. Additional funding from the Dirección General de Universidades e Investigación Comunidad de Madrid, Spain under the MOSSNOHO-CM program Grant No. S0505/ESP/0299 and from the Engineering and Physical Sciences EPSRC of the UK Grant Nos. GR/N20317, GR/N03358, GR/N35991, GR/R09497, and EP/E016340, the Joint Research Equipment Initiative JREI GR/M94427, and the Royal Society Wolfson Foundation refurbishment grant is also acknowledged. Finally we are grateful to the Royal Society for the award of a International Short Visit grant which has facilitated the collaborative work

Kinetic characterization of the critical step in HIV-1 protease maturation

HIV maturation requires multiple cleavage of long polyprotein chains into functional proteins that include the viral protease itself. Initial cleavage by the protease dimer occurs from within these precursors, and yet only a single protease monomer is embedded in each polyprotein chain. Self-activation has been proposed to start from a partially dimerized protease formed from monomers of different chains binding its own N termini by self-association to the active site, but a complete structural understanding of this critical step in HIV maturation is missing. Here, we captured the critical self-association of immature HIV-1 protease to its extended amino-terminal recognition motif using large-scale molecular dynamics simulations, thus confirming the postulated intramolecular mechanism in atomic detail. We show that self-association to a catalytically viable state requires structural cooperativity of the flexible β-hairpin “flap” regions of the enzyme and that the major transition pathway is first via self-association in the semiopen/open enzyme states, followed by enzyme conformational transition into a catalytically viable closed state. Furthermore, partial N-terminal threading can play a role in self-association, whereas wide opening of the flaps in concert with self-association is not observed. We estimate the association rate constant (k(on)) to be on the order of ∼1 × 10(4) s(−1), suggesting that N-terminal self-association is not the rate-limiting step in the process. The shown mechanism also provides an interesting example of molecular conformational transitions along the association pathway