Benchmark of Schemes for Multiscale Molecular Dynamics Simulations

In multiscale molecular dynamics simulations the accuracy of detailed models is combined with the efficiency of a reduced representation. For several applications - namely those of sampling enhancement - it is desirable to combine fine-grained (FG) and coarse-grained (CG) approaches into a single hybrid approach with an adjustable mixing parameter. We present a benchmark of three algorithms that use a mixing of the two representation layers using a Lagrangian formalism. The three algorithms use three different approaches for keeping the particles at the FG level of representation together: 1) addition of forces, 2) mass scaling, and 3) temperature scaling. The benchmark is applied to liquid hexadecane and includes an evaluation of the average configurational entropy of the FG and CG subsystems. The temperature-scaling scheme achieved a 3-fold sampling speedup with little deviation of FG properties. The addition-of-forces scheme kept FG properties the best but provided little sampling speedup. The mass-scaling scheme yielded a 5-fold speedup but deviated the most from FG properties

Vibrational Spectra of a Mechanosensitive Channel

We report the simulated vibrational spectra of a mechanosensitive membrane channel in different gating states. Our results show that while linear absorption is insensitive to structural differences, linear dichroism and sum-frequency generation spectroscopies are sensitive to the orientation of the transmembrane helices, which is changing during the opening process. Linear dichroism cannot distinguish an intermediate structure from the closed structure, but sum-frequency generation can. In addition, we find that two-dimensional infrared spectroscopy can be used to distinguish all three investigated gating states of the mechanosensitive membrane channel.

Bidirectional propagation of signals and nutrients in fungal networks via specialized hyphae

Intercellular distribution of nutrients and coordination of responses to internal and external cues via endogenous signaling molecules are hallmarks of multicellular organisms. Vegetative mycelia of multicellular fungi are syncytial networks of interconnected hyphae resulting from hyphal tip growth, branching, and fusion. Such mycelia can reach considerable dimensions and, thus, different parts can be exposed to quite different environmental conditions. Our knowledge about the mechanisms by which fungal mycelia can adjust nutrient gradients or coordinate their defense response to fungivores is scarce, in part due to limitations in technologies currently available for examining different parts of a mycelium over longer time periods at the microscopic level. Here, we combined a tailor-made microfluidic platform with time-lapse fluorescence microscopy to visualize the dynamic response of the vegetative mycelium of a basidiomycete to two different stimuli. The microfluidic platform allows simultaneous monitoring at both the colony and single-hypha level. We followed the dynamics of the distribution of a locally administered nutrient analog and the defense response to spatially confined predation by a fungivorous nematode. Although both responses of the mycelium were constrained locally, we observed long-distance propagation for both the nutrient analog and defense response in a subset of hyphae. This propagation along hyphae occurred in both acropetal and basipetal directions and, intriguingly, the direction was found to alternate every 3 hr in an individual hypha. These results suggest that multicellular fungi have, as of yet, undescribed mechanisms to coordinate the distribution of nutrients and their behavioral response upon attack by fungivores

Assessment of penetration of Ascorbyl Tetraisopalmitate into biological membranes by molecular dynamics

The present work, involves the simulation of the transport of a vitamin C derivative, Ascorbyl Tetraisopalmitate (ATI), through human skin by molecular dynamics. Percutaneous absorption of the ATI molecule through the infundibulum, an important route of absorption into the hair follicle of the human skin, has been modeled and compared with the stratum corneum membrane. The comparative study was done, using molecular dynamics with Martini force field. In infundibulum, a single ATI molecule require more time to penetrate, and the data obtained suggested that a high concentration of ATI molecule accelerated the process of penetration. In conclusion, the ATI molecule was found to have more affinity towards the stratum corneum as compared towards the infundibulum and it followed a straight pathway to penetrate (until 600 ns of simulation). In infundibulum, it showed less affinity, more mobility and followed a lateral pathway. Thus, this work contributes to a better understanding of the different molecular interactions during percutaneous absorption of active molecules in these two different types of biological membranes.The authors acknowledge financial support from the Brazilian agencies CAPES, Finep and Fapesp (Project FINEP 01.10.0661-00, FAPESP 2011/13250-0, FAPESP 2013/17247-9, FAPESP 2014/05975-2, CAPES 88887068264/2014-00), of Institute of Research and Development, University of Vale Paraíba

Combined systems approaches reveal highly plastic responses to antimicrobial peptide challenge in Escherichia coli

Obtaining an in-depth understanding of the arms races between peptides comprising the innate immune response and bacterial pathogens is of fundamental interest and will inform the development of new antibacterial therapeutics. We investigated whether a whole organism view of antimicrobial peptide (AMP) challenge on Escherichia coli would provide a suitably sophisticated bacterial perspective on AMP mechanism of action. Selecting structurally and physically related AMPs but with expected differences in bactericidal strategy, we monitored changes in bacterial metabolomes, morphological features and gene expression following AMP challenge at sub-lethal concentrations. For each technique, the vast majority of changes were specific to each AMP, with such a plastic response indicating E. coli is highly capable of discriminating between specific antibiotic challenges. Analysis of the ontological profiles generated from the transcriptomic analyses suggests this approach can accurately predict the antibacterial mode of action, providing a fresh, novel perspective for previous functional and biophysical studies

Polarizable Water Model for the Coarse-Grained MARTINI Force Field

Coarse-grained (CG) simulations have become an essential tool to study a large variety of biomolecular processes, exploring temporal and spatial scales inaccessible to traditional models of atomistic resolution. One of the major simplifications of CG models is the representation of the solvent, which is either implicit or modeled explicitly as a van der Waals particle. The effect of polarization, and thus a proper screening of interactions depending on the local environment, is absent. Given the important role of water as a ubiquitous solvent in biological systems, its treatment is crucial to the properties derived from simulation studies. Here, we parameterize a polarizable coarse-grained water model to be used in combination with the CG MARTINI force field. Using a three-bead model to represent four water molecules, we show that the orientational polarizability of real water can be effectively accounted for. This has the consequence that the dielectric screening of bulk water is reproduced. At the same time, we parameterized our new water model such that bulk water density and oil/water partitioning data remain at the same level of accuracy as for the standard MARTINI force field. We apply the new model to two cases for which current CG force fields are inadequate. First, we address the transport of ions across a lipid membrane. The computed potential of mean force shows that the ions now naturally feel the change in dielectric medium when moving from the high dielectric aqueous phase toward the low dielectric membrane interior. In the second application we consider the electroporation process of both an oil slab and a lipid bilayer. The electrostatic field drives the formation of water filled pores in both cases, following a similar mechanism as seen with atomistically detailed models

Improving Internal Peptide Dynamics in the Coarse-Grained MARTINI Model: Toward Large-Scale Simulations of Amyloid- and Elastin-like Peptides

We present an extension of the coarse-grained MARTINI model for proteins and apply this extension to amyloid- and elastin-like peptides. Atomistic simulations of tetrapeptides, octapeptides, and longer peptides in solution are used as a reference to parametrize a set of pseudodihedral potentials that describe the internal flexibility of MARTINI peptides. We assess the performance of the resulting model in reproducing various structural properties computed from atomistic trajectories of peptides in water. The addition of new dihedral angle potentials improves agreement with the contact maps computed from atomistic simulations significantly. We also address the question of which parameters derived from atomistic trajectories are transferable between different lengths of peptides. The modified coarse-grained model shows reasonable transferability of parameters for the amyloid- and elastin-like peptides. In addition, the improved coarse-grained model is also applied to investigate the self-assembly of β-sheet forming peptides on the microsecond time scale. The octapeptides SNNFGAIL and (GV)4 are used to examine peptide aggregation in different environments, in water, and at the water–octane interface. At the interface, peptide adsorption occurs rapidly, and peptides spontaneously aggregate in favor of stretched conformers resembling β-strands