Multi-scale simulation reveals that an amino acid substitution increases photosensitizing reaction inputs in Rhodopsins.

Evaluating the availability of molecular oxygen (O2 ) and energy of excited states in the retinal binding site of rhodopsin is a crucial challenging first step to understand photosensitizing reactions in wild-type (WT) and mutant rhodopsins by absorbing visible light. In the present work, energies of the ground and excited states related to 11-cis-retinal and the O2 accessibility to the ß-ionone ring are evaluated inside WT and human M207R mutant rhodopsins. Putative O2 pathways within rhodopsins are identified by using molecular dynamics simulations, Voronoi-diagram analysis, and implicit ligand sampling while retinal energetic properties are investigated through density functional theory, and quantum mechanical/molecular mechanical methods. Here, the predictions reveal that an amino acid substitution can lead to enough energy and O2 accessibility in the core hosting retinal of mutant rhodopsins to favor the photosensitized singlet oxygen generation, which can be useful in understanding retinal degeneration mechanisms and in designing blue-lighting-absorbing proteic photosensitizers.

Multiscale Simulations of Clavulanate Inhibition Identify the Reactive Complex in Class A ß-Lactamases and Predict the Efficiency of Inhibition.

Clavulanate is used as an effective drug in combination with ß-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we perform combined quantum mechanics/molecular mechanics simulations of several covalent complexes of clavulanate with class A ß-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as being responsible for inhibition. Further, the obtained free energy barriers discriminate clinically relevant inhibition (TEM-1) from less effective inhibition (KPC-2).