Alchemical Free Energy Calculations on Membrane-Associated Proteins.

Membrane proteins have diverse functions within cells and are well-established drug targets. The advances in membrane protein structural biology have revealed drug and lipid binding sites on membrane proteins, while computational methods such as molecular simulations can resolve the thermodynamic basis of these interactions. Particularly, alchemical free energy calculations have shown promise in the calculation of reliable and reproducible binding free energies of protein-ligand and protein-lipid complexes in membrane-associated systems. In this review, we present an overview of representative alchemical free energy studies on G-protein-coupled receptors, ion channels, transporters as well as protein-lipid interactions, with emphasis on best practices and critical aspects of running these simulations. Additionally, we analyze challenges and successes when running alchemical free energy calculations on membrane-associated proteins. Finally, we highlight the value of alchemical free energy calculations calculations in drug discovery and their applicability in the pharmaceutical industry.

Zwitterions Functionalized by Optical Cycling Centers: Toward Laser-Coolable Polyatomic Molecular Cations.

Functionalization of large aromatic compounds and biomolecules with optical cycling centers (OCC) is of considerable interest for the design and engineering of molecules with a highly selective optical photoresponse. Both internal and external dynamics in such molecules can be precisely controlled by lasers, enabling their efficient cooling and opening up broad prospects for high-precision spectroscopy, ultracold chemistry, enantiomer separation, and various other fields. The way the OCC is bonded to a molecular ligand is crucial to the optical properties of the OCC, first of all, for the degree of closure of the optical cycling loop. Here we introduce a novel type of functionalized molecular cation where a positively charged OCC is bonded to various organic zwitterions with a particularly high permanent dipole moment. We consider strontium(I) complexes with betaine and other zwitterionic ligands and show the possibility of creating efficient and highly closed population cycling for dipole-allowed optical transitions in such complexes.