The chemical property of methyl groups that renders them indispensable to biomolecules is their hydrophobicity. Quantum mechanical studies undertaken here to understand the effect of point substitutions on potassium (K-) channels illustrate quantitatively how methyl-induced polarization also contributes to biomolecular function. K- channels regulate transmembrane salt concentration gradients by transporting K ⁺ ions selectively. One of the K ⁺ binding sites in the channel’s selectivity filter, the S4 site, also binds Ba ²⁺ ions, which blocks K ⁺ transport. This inhibitory property of Ba ²⁺ ions has been vital in understanding K-channel mechanism. In most K-channels, the S4 site is composed of four threonine amino acids. The K channels that carry serine instead of threonine are significantly less susceptible to Ba ²⁺ block and have reduced stabilities. We find that these differences can be explained by the lower polarizability of serine compared with threonine, because serine carries one less branched methyl group than threonine. A T→S substitution in the S4 site reduces its polarizability, which, in turn, reduces ion binding by several kilocalories per mole. Although the loss in binding affinity is high for Ba ²⁺ , the loss in K ⁺ binding affinity is also significant thermodynamically, which reduces channel stability. These results highlight, in general, how biomolecular function can rely on the polarization induced by methyl groups, especially those that are proximal to charged moieties, including ions, titratable amino acids, sulfates, phosphates, and nucleotides.

Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) has caused substantially more infections, deaths, and economic disruptions than the 2002‐2003 SARS‐CoV. The key to understanding SARS‐CoV‐2's higher infectivity lies partly in its host receptor recognition mechanism. Experiments show that the human angiotensin converting enzyme 2 (ACE2) protein, which serves as the primary receptor for both CoVs, binds to the receptor binding domain (RBD) of CoV‐2's spike protein stronger than SARS‐CoV's spike RBD. The molecular basis for this difference in binding affinity, however, remains unexplained from X‐ray structures. To go beyond insights gained from X‐ray structures and investigate the role of thermal fluctuations in structure, we employ all‐atom molecular dynamics simulations. Microseconds‐long simulations reveal that while CoV and CoV‐2 spike‐ACE2 interfaces have similar conformational binding modes, CoV‐2 spike interacts with ACE2 via a larger combinatorics of polar contacts, and on average, makes 45% more polar contacts. Correlation analysis and thermodynamic calculations indicate that these differences in the density and dynamics of polar contacts arise from differences in spatial arrangements of interfacial residues, and dynamical coupling between interfacial and non‐interfacial residues. These results recommend that ongoing efforts to design spike‐ACE2 peptide blockers will benefit from incorporating dynamical information as well as allosteric coupling effects.

Quasi-chemical theory applied to ion hydration combines statistical mechanical theory, electronic structure calculations, and molecular simulation, disciplines which are individually subjects for specialized professional attention. Because it combines activities which are themselves non-trivial, quasi-chemical theory is typically viewed with surprise. Nevertheless, it provides a fully-considered framework for analysis of ion hydration. Furthermore, the initial calculations are indeed simple, successful, and provide new information to long-standing experimental activities such as neutron diffraction by hydrated ions. Here we review quasi-chemical theory in the context of a challenging application, Rb⁺(aq).