A pH-Dependent Coarse-Grained Model for Disordered Proteins: Histidine Interactions Modulate Conformational Ensembles.

Histidine (His) presents a unique challenge for modeling disordered protein conformations, as it is versatile and occurs in both the neutral (His) and positively charged (His) states. These His charge states, which are enabled by its imidazole side chain, influence the electrostatic and short-range interactions of His residues, which potentially engage in cation-π, π-π, and charge-charge interactions. Existing coarse-grained (CG) models often simplify His representation by assigning it an average charge, thereby neglecting these potential short-range interactions.

Aromatic Residues in Proteins: Re-Evaluating the Geometry and Energetics of π-π, Cation-π, and CH-π Interactions.

Aromatic residues can participate in various biomolecular interactions, such as π-π, cation-π, and CH-π interactions, which are essential for protein structure and function. Here, we re-evaluate the geometry and energetics of these interactions using quantum mechanical (QM) calculations, focusing on pairwise interactions involving the aromatic amino acids Phe, Tyr, and Trp and the cationic amino acids Arg and Lys. Our findings reveal that π-π interactions, while energetically favorable, are less abundant in structured proteins than commonly assumed and are often overshadowed by previously underappreciated, yet prevalent, CH-π interactions.

The structure of the Lujo virus spike complex.

Lujo virus (LUJV) is a human pathogen that was the cause of a deadly hemorrhagic fever outbreak in Africa. LUJV is a divergent member of the Arenaviridae with some similarities to both the "Old World" and "New World" serogroups, but it uses a cell-entry receptor, neuropilin-2 (NRP2), that is distinct from the receptors of OW and NW viruses. Though the receptor binding domain of LUJV has been characterized structurally, the overall organization of the trimeric spike complex and how NRP2 is recognized in this context were unknown.

Histidine in Proteins: pH-Dependent Interplay between π-π, Cation-π, and CH-π Interactions.

Histidine (His) stands out as the most versatile natural amino acid due to its side chain's facile propensity to protonate at physiological pH, leading to a transition from aromatic to cationic characteristics and thereby enabling diverse biomolecular interactions. In this study, our objective was to quantify the energetics and geometries of pairwise interactions involving His at varying pH levels. Through quantum chemical calculations, we discovered that His exhibits robust participation in both π-π and cation-π interactions, underscoring its ability to adopt a π or cationic nature, akin to other common residues.

Benefits of Range-Separated Hybrid and Double-Hybrid Functionals for a Large and Diverse Data Set of Reaction Energies and Barrier Heights.

To better understand the thermochemical kinetics and mechanism of a specific chemical reaction, an accurate estimation of barrier heights (forward and reverse) and reaction energies is vital. Because of the large size of reactants and transition state structures involved in real-life mechanistic studies (e.g.