The Role of General Acid Catalysis in the Mechanism of an Alkyl Transferase Ribozyme.

MTR1 is an in vitro-selected alkyl transferase ribozyme that transfers an alkyl group from -alkylguanine to N1 of the target adenine in the RNA substrate (A63). The structure of the ribozyme suggested a mechanism in which a cytosine (C10) acts as a general acid to protonate -alkylguanine N1. Here, we have analyzed the role of the C10 general acid and the A63 nucleophile by atomic mutagenesis and computation.

Assessing variations in care delivered to rural out of hospital cardiac arrest patients in the interfacility transfer setting.

Objective: There is significant variation in out-of-hospital cardiac arrest (OHCA) outcomes between different regions. We sought to evaluate outcomes of OHCA patients in the interfacility transfer (IFT) setting, between critical care transport (LifeFlight) and community Emergency Medical Services (EMS), in the state of Maine.

Methods: This was a retrospective analysis of our institution's electronic medical record and the Maine EMS database.

Improvements in Precision of Relative Binding Free Energy Calculations Afforded by the Alchemical Enhanced Sampling (ACES) Approach.

Accurate predictions of how strongly small molecules bind to proteins, such as those afforded by relative binding free energy (RBFE) calculations, can greatly increase the efficiency of the hit-to-lead and lead optimization stages of the drug discovery process. The success of such calculations, however, relies heavily on their precision. Here, we show that a recently developed alchemical enhanced sampling (ACES) approach can consistently improve the precision of RBFE calculations on a large and diverse set of proteins and small molecule ligands.