Revolution and the rule of law: Dicey on Irish Home Rule

Dicey came close to acknowledging a legitimate right to separatist revolution for Ireland but rejected Home Rule as an illegitimate attempt to revolutionist the British constitution

Structure and Function in Homodimeric Enzymes:Simulations of Cooperative and Independent Functional Motions

Large-scale conformational change is a common feature in the catalytic cycles of enzymes. Many enzymes function as homodimers with active sites that contain elements from both chains. Symmetric and anti-symmetric cooperative motions in homodimers can potentially lead to correlated active site opening and/or closure, likely to be important for ligand binding and release. Here, we examine such motions in two different domain-swapped homodimeric enzymes: the DcpS scavenger decapping enzyme and citrate synthase. We use and compare two types of all-atom simulations: conventional molecular dynamics simulations to identify physically meaningful conformational ensembles, and rapid geometric simulations of flexible motion, biased along normal mode directions, to identify relevant motions encoded in the protein structure. The results indicate that the opening/closure motions are intrinsic features of both unliganded enzymes. In DcpS, conformational change is dominated by an anti-symmetric cooperative motion, causing one active site to close as the other opens; however a symmetric motion is also significant. In CS, we identify that both symmetric (suggested by crystallography) and asymmetric motions are features of the protein structure, and as a result the behaviour in solution is largely non-cooperative. The agreement between two modelling approaches using very different levels of theory indicates that the behaviours are indeed intrinsic to the protein structures. Geometric simulations correctly identify and explore large amplitudes of motion, while molecular dynamics simulations indicate the ranges of motion that are energetically feasible. Together, the simulation approaches are able to reveal unexpected functionally relevant motions, and highlight differences between enzymes

An Efficient Computational Assay for β-Lactam Antibiotic Breakdown by Class A β-Lactamases

Breakdown of β-lactam antibiotics by β-lactamases is one of the most common resistance mechanisms against these drugs. Here, we present a computationally efficient combined quantum mechanics/molecular mechanics simulation protocol for hydrolysis of the β-lactamase acylenzyme with meropenem, a carbapenem antibiotic. Starting from the previously published computational assay, we have successfully reduced both the conformational space and the sampling time, which leads to a more than 99% reduction on computer resources needed for this assay (less than 24 CPU hours per reaction). This simplified in silico protocol distinguishes accurately between class A β-lactamases that are able or unable to break down carbapenems. We further demonstrate that these protocols can be used to elucidate mechanistic details of β-lactam breakdown. The new efficient computational assaymay be used to predict carbapenem hydrolytic activity of new β-lactamase variants as they arise, and in identifying routes to development of new, more resilient β-lactam antibiotics or new generations of mechanism-based β-lactamase inhibitors.</div

From So Far to So Close. Addressing the Refugee Phenomenon: History, Sociology, Technology

European project Enhancing Social Cohesion through Sharing the Cultural Heritage of Forced Migrations - SO-CLOSELa Conferència internacional "From So Far to So Close. Addressing the Refugee Phenomenon: History, Sociology, Technology" es va celebrar en format virtual els dies 15 i 16 de juny de 2020. La primera taula rodona "History of Refugees in the 20th Century" va incloure les següents intervencions: 1. Violence, Civil War and Female Forced Displacement : the case of Trikeri (Greece) / Magda Fitili -- 2. After the war. Communist mass violence and forced displacements in Eastern Europe after 1945 / Virgiliu Ţârău -- 3. Mass Violence and Displacement during the 1990s from former Yugoslavia: On Overview with a focus onBosnia and Herzegovina / Dženeta Karabegović -

QM/MM simulations as an assay for carbapenemase activity in class A β-lactamases

Carbapenemases are distinguished from carbapenem-inhibited β-lactamases with a protocol involving QM/MM free energy simulations of acyl–enzyme deacylation, requiring only the enzyme 3D structure as input.</p