The High Energy Density Scientific Instrument at the European XFEL.

The European XFEL delivers up to 27000 intense (>10 photons) pulses per second, of ultrashort (≤50 fs) and transversely coherent X-ray radiation, at a maximum repetition rate of 4.5 MHz. Its unique X-ray beam parameters enable groundbreaking experiments in matter at extreme conditions at the High Energy Density (HED) scientific instrument.

The impact of transforming care on the care and safety of patients with intellectual disabilities and forensic needs.

NHS England recently published a national plan to develop community services for people with intellectual disabilities and autism who display challenging behaviour by using resources from the closure of a large number of hospital beds. An ambitious timescale has been set to implement this plan. The bed closure programme is moving ahead rapidly, but there has been little progress in developing community services to support it.

Using Structural Kinetic Modeling To Identify Key Determinants of Stability in Reaction Networks.

Kinetic modeling is increasingly used to understand the reaction dynamics of metabolic systems. However, one major drawback of kinetic modeling is that appropriate rate parameters required to implement such models are often unavailable. To circumvent this limitation, an approach known as structural kinetic modeling was developed as a way to understand the dynamics of reaction networks without explicitly requiring rate parameters.

Molecular simulations to delineate functional conformational transitions in the HCV polymerase.

Hepatitis C virus (HCV) is a global health concern for which there is no vaccine available. The HCV polymerase is responsible for the critical function of replicating the RNA genome of the virus. Transitions between at least two conformations (open and closed) are necessary to allow the enzyme to replicate RNA.

Current advances in molecular, biochemical, and computational modeling analysis of microalgal triacylglycerol biosynthesis.

Triacylglycerols (TAGs) are highly reduced energy storage molecules ideal for biodiesel production. Microalgal TAG biosynthesis has been studied extensively in recent years, both at the molecular level and systems level through experimental studies and computational modeling. However, discussions of the strategies and products of the experimental and modeling approaches are rarely integrated and summarized together in a way that promotes collaboration among modelers and biologists in this field.

Computational predictions suggest that structural similarity in viral polymerases may lead to comparable allosteric binding sites.

The identification of ligand-binding sites is often the first step in drug targeting and design. To date there are numerous computational tools available to predict ligand binding sites. These tools can guide or mitigate the need for experimental methods to identify binding sites, which often require significant resources and time.

Using the Hepatitis C Virus RNA-Dependent RNA Polymerase as a Model to Understand Viral Polymerase Structure, Function and Dynamics.

Viral polymerases replicate and transcribe the genomes of several viruses of global health concern such as Hepatitis C virus (HCV), human immunodeficiency virus (HIV) and Ebola virus. For this reason they are key targets for therapies to treat viral infections. Although there is little sequence similarity across the different types of viral polymerases, all of them present a right-hand shape and certain structural motifs that are highly conserved.

Dual Allosteric Inhibitors Jointly Modulate Protein Structure and Dynamics in the Hepatitis C Virus Polymerase.

The hepatitis C virus (HCV) infects close to 200 million people globally, resulting in a significant need for effective HCV therapies. The HCV polymerase (gene product NS5B) is a valuable target for therapeutics because of its role in replicating the viral genome. Various studies have identified inhibitors for this enzyme, including non-nucleoside inhibitors (NNIs) that bind distal to the enzyme active site.

Allosteric inhibitors have distinct effects, but also common modes of action, in the HCV polymerase.

The RNA-dependent RNA polymerase from the Hepatitis C Virus (gene product NS5B) is a validated drug target because of its critical role in genome replication. There are at least four distinct allosteric sites on the polymerase to which several small molecule inhibitors bind. In addition, numerous crystal structures have been solved with different allosteric inhibitors bound to the polymerase.

Molecular simulations illuminate the role of regulatory components of the RNA polymerase from the hepatitis C virus in influencing protein structure and dynamics.

The RNA polymerase (gene product NS5B) from the hepatitis C virus is responsible for replication of the viral genome and is a validated drug target for new therapeutic agents. NS5B has a structure resembling an open right hand (containing the fingers, palm, and thumb subdomains), a hydrophobic C-terminal region, and two magnesium ions coordinated in the palm domain. Biochemical data suggest that the magnesium ions provide structural stability and are directly involved in catalysis, while the C-terminus plays a regulatory role in NS5B function.

Inhibitors for the hepatitis C virus RNA polymerase explored by SAR with advanced machine learning methods.

Hepatitis C virus (HCV) is a global health challenge, affecting approximately 200 million people worldwide. In this study we developed SAR models with advanced machine learning classifiers Random Forest and k Nearest Neighbor Simulated Annealing for 679 small molecules with measured inhibition activity for NS5B genotype 1b. The activity was expressed as a binary value (active/inactive), where actives were considered molecules with IC50 ≤0.

Thumb inhibitor binding eliminates functionally important dynamics in the hepatitis C virus RNA polymerase.

Hepatitis C virus (HCV) has infected almost 200 million people worldwide, typically causing chronic liver damage and severe complications such as liver failure. Currently, there are few approved treatments for viral infection. Thus, the HCV RNA-dependent RNA polymerase (gene product NS5B) has emerged as an important target for small molecule therapeutics.

Exploration of transferability in multiscale coarse-grained peptide models.

Coarse-grained models can facilitate the efficient simulation of complex biological systems. In earlier studies the multiscale coarse-graining (MS-CG) method was employed to examine the folding landscape for two small peptides. In those studies, MS-CG force fields specific to each peptide were employed.

Conformational switching between protein substates studied with 2D IR vibrational echo spectroscopy and molecular dynamics simulations.

Myoglobin is an important protein for the study of structure and dynamics. Three conformational substates have been identified for the carbonmonoxy form of myoglobin (MbCO). These are manifested as distinct peaks in the IR absorption spectrum of the CO stretching mode.

Molecular description of flexibility in an antibody combining site.

Mature antibodies (Abs) that are exquisitely specific for virtually any foreign molecule may be produced by affinity maturation of naïve (or germline) Abs. However, the finite number of germline Abs available suggests that, in contrast to mature Abs, germline Abs must be broadly polyspecific so that they are able to recognize a wide range of ligands. Thus, affinity maturation must play a role in mediating Ab specificity.

Peptide folding using multiscale coarse-grained models.

The multiscale coarse-graining (MS-CG) method has been previously used to describe the equilibrium properties of peptides. The present study reveals that MS-CG models of alpha-helical polyalanine and the beta-hairpin V 5PGV 5 possess the capacity to efficiently refold in simulations initiated from unfolded configurations. The MS-CG peptides exhibit free energy landscapes that are funneled toward folded configurations and two-state folding behavior, consistent with the known characteristics of small, rapidly folding peptides.

Origins of enhanced proton transport in the Y7F mutant of human carbonic anhydrase II.

Human carbonic anhydrase II (HCA II), among the fastest enzymes known, catalyzes the reversible hydration of CO 2 to HCO 3 (-). The rate-limiting step of this reaction is believed to be the formation of an intramolecular water wire and transfer of a proton across the active site cavity from a zinc-bound solvent to a proton shuttling residue (His64). X-ray crystallographic studies have shown this intramolecular water wire to be directly stabilized through hydrogen bonds via a small well-defined set of amino acids, namely, Tyr7, Asn62, Asn67, Thr199, and Thr200.

Molecular evolution of affinity and flexibility in the immune system.

The immune system responds to the introduction of foreign antigens by rapidly evolving antibodies with increasing affinity for the antigen (i.e., maturation).

Coarse-grained peptide modeling using a systematic multiscale approach.

A systematic new approach to derive multiscale coarse-grained (MS-CG) models has been recently developed. The approach employs information from atomistically detailed simulations to derive CG forces and associated effective potentials. In this work, the MS-CG methodology is extended to study two peptides representing distinct structural motifs, alpha-helical polyalanine and the beta-hairpin V(5)PGV(5).

Antibody evolution constrains conformational heterogeneity by tailoring protein dynamics.

The evolution of proteins with novel function is thought to start from precursor proteins that are conformationally heterogeneous. The corresponding genes may be duplicated and then mutated to select and optimize a specific conformation. However, testing this idea has been difficult because of the challenge of quantifying protein flexibility and conformational heterogeneity as a function of evolution.

Evaluating the conformational entropy of macromolecules using an energy decomposition approach.

We have developed a novel method to compute the conformational entropy of any molecular system via conventional simulation techniques. This method only requires that the total energy of the system is available and that the Hamiltonian is separable, with individual energy terms for the various degrees of freedom. Consequently the method, which we call the energy decomposition (Edcp) approach, is general and applicable to any large polymer in implicit solvent.

Conformational substates modulate hydride transfer in dihydrofolate reductase.

In earlier studies of the hydride-transfer reaction catalyzed by dihydrofolate reductase (DHFR) we identified features of the protein correlated with variations in the reaction barrier. We extend the scope of those studies by carrying out potential of mean force (PMF) simulations to determine the hydride-transfer barrier in the wild-type protein as well as the G121V and G121S mutants. While our prior studies focused on the reactant state, our current work addresses the full reaction pathway and directly probes the reactive event.

The coupling of structural fluctuations to hydride transfer in dihydrofolate reductase.

The energy barrier for hydride transfer in wild-type G121V and G121S variants of Escherichia coli dihydrofolate reductase (DHFR) fluctuates in a time-dependent manner. This fluctuation may be attributed to structural changes in the protein that modulate the site of chemistry. Despite being far from the active site, mutations at position 121 of DHFR reduce the hydride transfer rate of the enzyme.