Redefining the Limits of Functional Continuity in the Early Evolution of P-Loop NTPases.

At the heart of many nucleoside triphosphatases is a conserved phosphate-binding sequence motif. A current model of early enzyme evolution proposes that this 6-8 residue motif could have sparked the emergence of the very first nucleoside triphosphatases - a striking example of evolutionary continuity from simple beginnings, if true. To test this provocative model, seven disembodied Walker A-derived peptides were extensively computationally characterized.

Targeting MarA N-terminal domain dynamics to prevent DNA binding.

Efflux is one of the mechanisms employed by Gram-negative bacteria to become resistant to routinely used antibiotics. The inhibition of efflux by targeting their regulators is a promising strategy to re-sensitize bacterial pathogens to antibiotics. AcrAB-TolC is the main resistance-nodulation-division efflux pump in Enterobacteriaceae.

The winter holidays are glorious-except when they're not.

The winter holidays are a time to celebrate, but can be oppressive for those who cannot. It is therefore important to look after trainees and colleagues who miss their loved ones on Christmas day. [Image: see text]

Using residue interaction networks to understand protein function and evolution and to engineer new proteins.

Residue interaction networks (RINs) provide graph-based representations of interaction networks within proteins, providing important insight into the factors driving protein structure, function, and stability relationships. There exists a wide range of tools with which to perform RIN analysis, taking into account different types of interactions, input (crystal structures, simulation trajectories, single proteins, or comparative analysis across proteins), as well as formats, including standalone software, web server, and a web application programming interface (API). In particular, the ability to perform comparative RIN analysis across protein families using "metaRINs" provides a valuable tool with which to dissect protein evolution.

Catalytic Redundancies and Conformational Plasticity Drives Selectivity and Promiscuity in Quorum Quenching Lactonases.

Several enzymes from the metallo-β-lactamase-like family of lactonases (MLLs) degrade acyl L-homoserine lactones (AHLs). They play a role in a microbial communication system known as quorum sensing, which contributes to pathogenicity and biofilm formation. Designing quorum quenching () enzymes that can interfere with this communication allows them to be used in a range of industrial and biomedical applications.

Conformational Modulation of a Mobile Loop Controls Catalysis in the (βα)-Barrel Enzyme of Histidine Biosynthesis HisF.

The overall significance of loop motions for enzymatic activity is generally accepted. However, it has largely remained unclear whether and how such motions can control different steps of catalysis. We have studied this problem on the example of the mobile active site βα-loop (loop1) of the (βα)-barrel enzyme HisF, which is the cyclase subunit of imidazole glycerol phosphate synthase.

SHP-1 Variants Broaden the Understanding of pH-Dependent Activities in Protein Tyrosine Phosphatases.

The protein tyrosine phosphatase (PTP) SHP-1 plays an important role in both immune regulation and oncogenesis. This enzyme is part of a broader family of PTPs that all play important regulatory roles in vivo. Common to these enzymes is a highly conserved aspartic acid (D421 in SHP-1) that acts as an acid/base catalyst during the PTP-catalyzed reaction.

Mandatory national language requirements in higher education.

Some countries try to curb internationalisation in academia or require that foreign scientists take language courses. While this is done for the wrong reasons, learning the language of the host country has great benefits for academic staff. [Image: see text]

Friends and relatives: insight into conformational regulation from orthologues and evolutionary lineages using KIF and KIN.

Noncovalent interaction networks provide a powerful means to represent and analyze protein structure. Such networks can represent both static structures and dynamic conformational ensembles. We have recently developed two tools for analyzing such interaction networks and generating hypotheses for protein engineering.

In vitro fertilization and the ethics of frozen embryos.

The Alabama Supreme Court decision to consider embryos as children sheds light on a growing problem for IVF clinics: what to do with the increasing number of frozen surplus embryos? [Image: see text]

Catalytic Redundancies and Conformational Plasticity Drives Selectivity and Promiscuity in Quorum Quenching Lactonases.

Several enzymes from the metallo-β-lactamase-like family of lactonases (MLLs) degrade acyl-L-homoserine lactones (AHLs). In doing so, they play a role in a microbial communication system, quorum sensing, which contributes to pathogenicity and biofilm formation. There is currently great interest in designing quorum quenching ( ) enzymes that can interfere with this communication and be used in a range of industrial and biomedical applications.

Sequence - dynamics - function relationships in protein tyrosine phosphatases.

Protein tyrosine phosphatases (PTPs) are crucial regulators of cellular signaling. Their activity is regulated by the motion of a conserved loop, the WPD-loop, from a catalytically inactive open to a catalytically active closed conformation. WPD-loop motion optimally positions a catalytically critical residue into the active site, and is directly linked to the turnover number of these enzymes.

Key interaction networks: Identifying evolutionarily conserved non-covalent interaction networks across protein families.

Protein structure (and thus function) is dictated by non-covalent interaction networks. These can be highly evolutionarily conserved across protein families, the members of which can diverge in sequence and evolutionary history. Here we present KIN, a tool to identify and analyze conserved non-covalent interaction networks across evolutionarily related groups of proteins.

The ineligibility barrier for international researchers in US academia.

Many grants from US funding agencies are restricted to US citizens or permanent residents which negatively impacts the career options for foreign scientists working in the USA. [Image: see text]

How to write a successful graduate school application.

Practical advice for prospective graduate students on how to apply for a PhD position in the USA and Europe. [Image: see text]

Correction to "Micelle Maker: An Online Tool for Generating Equilibrated Micelles as Direct Input for Molecular Dynamics Simulations".

[This corrects the article DOI: 10.1021/acsomega.7b00820.

A sensor complements the steric gate when DNA polymerase ϵ discriminates ribonucleotides.

The cellular imbalance between high concentrations of ribonucleotides (NTPs) and low concentrations of deoxyribonucleotides (dNTPs), is challenging for DNA polymerases when building DNA from dNTPs. It is currently believed that DNA polymerases discriminate against NTPs through a steric gate model involving a clash between a tyrosine and the 2'-hydroxyl of the ribonucleotide in the polymerase active site in B-family DNA polymerases. With the help of crystal structures of a B-family polymerase with a UTP or CTP in the active site, molecular dynamics simulations, biochemical assays and yeast genetics, we have identified a mechanism by which the finger domain of the polymerase sense NTPs in the polymerase active site.

Representation matters: responding to the current campaign against DEI efforts.

Abandonment of diversity, equity and inclusion programs undermines fairness and the productivity of research.

Science after Brexit: bright spots on the Horizon?

Is scientific partnership between the UK and EU on the Horizon?

Loop dynamics and the evolution of enzyme activity.

In the early 2000s, Tawfik presented his 'New View' on enzyme evolution, highlighting the role of conformational plasticity in expanding the functional diversity of limited repertoires of sequences. This view is gaining increasing traction with increasing evidence of the importance of conformational dynamics in both natural and laboratory evolution of enzymes. The past years have seen several elegant examples of harnessing conformational (particularly loop) dynamics to successfully manipulate protein function.

KIF-Key Interactions Finder: A program to identify the key molecular interactions that regulate protein conformational changes.

Simulation datasets of proteins (e.g., those generated by molecular dynamics simulations) are filled with information about how a non-covalent interaction network within a protein regulates the conformation and, thus, function of the said protein.