Finding Multiple Reaction Pathways of Ligand Unbinding

Searching for reaction pathways describing rare events in large systems presents a long-standing challenge in chemistry and physics. Incorrectly computed reaction pathways result in the degeneracy of microscopic configurations and inability to sample hidden energy barriers. To this aim, we present a general enhanced sampling method to find multiple diverse reaction pathways of ligand unbinding through non-convex optimization of a loss function describing ligand-protein interactions. The method successfully overcomes large energy barriers using an adaptive bias potential, and constructs possible reaction pathways along transient tunnels without the initial guesses of intermediate or final states, requiring crystallographic information only. We examine the method on the T4 lysozyme L99A mutant which is often used as a model system to study ligand binding to proteins, provide a previously unknown reaction pathway, and show that using the bias potential and the tunnel widths it is possible to capture heterogeneity of the unbinding mechanisms between the found transient protein tunnels

Gas-Phase Retinal Spectroscopy: Temperature Effects Are But a Mirage

We employ state-of-the-art first-principle approaches to investigate whether temperature effects are responsible for the unusually broad and flat spectrum of protonated Schiff base retinal observed in photodissociation spectroscopy, as has recently been proposed. We first carefully calibrate how to construct a realistic geometrical model of retinal and show that the exchange–correlation M06-2X functional yields an accurate description while the commonly used complete active space self-consistent field method (CASSCF) is not adequate. Using modern multiconfigurational perturbative methods (NEVPT2) to compute the excitations, we then demonstrate that conformations with different orientations of the β-ionone ring are characterized by similar excitations. Moreover, other degrees of freedom identified as active in room-temperature molecular dynamics simulations do not yield the shift required to explain the anomalous spectral shape. Our findings indicate that photodissociation experiments are not representative of the optical spectrum of retinal in the gas phase and call for further experimental characterization of the dissociation spectr

Excitation energies of retinal chromophores: Critical role of the structural model

We employ a variety of highly-correlated approaches including quantum Monte Carlo (QMC) and the n-electron valence state perturbation theory (NEVPT2) to compute the vertical excitation energies of retinal protonated Schiff base (RPSB) models in the gas phase. We find that the NEVPT2 excitation energies are in good agreement with the QMC values and confirm our previous findings that the complete-active-space perturbation (CASPT2) approach yields accurate excitations for RPSB models only when the more recent zero-order IPEA Hamiltonian is employed. The excitations computed with the original zero-order formulation of CASPT2 are instead systematically red-shifted by more than 0.3 eV. We then focus on the full 11-cis retinal chromophore and show that the M06-2X and MP2 approaches provide reliable ground-state equilibrium structures for this system while the complete-active-space self-consistent field (CASSCF) geometry is characterized by significantly higher ground-state energies at the NEVPT2 and CASPT2 level. Our calibration of the structural model together with the general agreement of all highly-correlated excited-state methods allows us to reliably assign a value of about 2.3 eV to the vertical excitation of 11-cis RPSB in the gas-phase

Surveillance of Ruminant Diseases in the Nordic Countries

<p/> <p>All the Nordic countries have a basis for their surveillance and disease control in ruminants in national legislation and regulations listing notifiable diseases of concern to the countries. The Nordic countries are a disease-free zone comparing to other parts of the world and the aim of the surveillance is to keep that status and be able to document it. Following is a short summary from each country.</p

Hringja - hnoða : tillaga að einfölduðum viðbrögðum almennings við hjartastoppi utan sjúkrahúss

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn Skoða/Opna(view/open)Hjartastopp hjá fullorðnum er í miklum meirihluta tilfella orsakað af sleglahraðtakti (ventricular tachycardia) eða sleglatifi (ventricular fibrillation). Ef sleglatif er orsökin er rafstuð á brjóstholið það eina sem dugar til að koma aftur á reglulegum sínustakti. Þegar hjartastopp verða utan sjúkrahúss líður hins vegar oft einhver tími þar til rafstuðsgjafi kemur á vettvang, yfirleitt með sjúkrabifreið. Ef vitni eru að hjartastoppi utan sjúkrahúss skiptir gríðarlega miklu máli að hefja grunnendurlífgun sem allra fyrst eftir að kallað hefur verið á aðstoð. Slík viðbrögð geta lengt þann tíma sem sjúklingur er í sleglatifi eða sleglahraðtakti og auka þannig líkur á að mögulegt sé að koma aftur á sínustakti með rafstuði (1). Jafnframt getur þetta dregið úr hættu á heilaskaða ef einstaklingurinn lifir hjartastoppið af (2). Mikilvægi þess er augljóst þar sem hæfni þeirra sem lifa af hjartastopp fer að miklu leyti eftir því hvort heilastarfsemi hefur orðið fyrir varanlegum skaða eða ekki

Analyzing and Biasing Simulations with PLUMED

This chapter discusses how the PLUMED plugin for molecular dynamics can be used to analyze and bias molecular dynamics trajectories. The chapter begins by introducing the notion of a collective variable and by then explaining how the free energy can be computed as a function of one or more collective variables. A number of practical issues mostly around periodic boundary conditions that arise when these types of calculations are performed using PLUMED are then discussed. Later parts of the chapter discuss how PLUMED can be used to perform enhanced sampling simulations that introduce simulation biases or multiple replicas of the system and Monte Carlo exchanges between these replicas. This section is then followed by a discussion on how free-energy surfaces and associated error bars can be extracted from such simulations by using weighted histogram and block averaging techniques

Shared Metadata for Data-Centric Materials Science

The expansive production of data in materials science, their widespread sharing and repurposing requires educated support and stewardship. In order to ensure that this need helps rather than hinders scientific work, the implementation of the FAIR-data principles (Findable, Accessible, Interoperable, and Reusable) must not be too narrow. Besides, the wider materials-science community ought to agree on the strategies to tackle the challenges that are specific to its data, both from computations and experiments. In this paper, we present the result of the discussions held at the workshop on "Shared Metadata and Data Formats for Big-Data Driven Materials Science". We start from an operative definition of metadata, and what features a FAIR-compliant metadata schema should have. We will mainly focus on computational materials-science data and propose a constructive approach for the FAIRification of the (meta)data related to ground-state and excited-states calculations, potential-energy sampling, and generalized workflows. Finally, challenges with the FAIRification of experimental (meta)data and materials-science ontologies are presented together with an outlook of how to meet them