The water molecule arrangement over the side chain of some aliphatic amino acids: A quantum chemical and bottom‐up investigation

Abstract

The geometry of surrounding water molecules on the side chain of glycine, alanine, α‐aminoisobutyric acid, α‐aminobutyric acid, valine, and related hydrocarbons has been analyzed combining bottom‐up and quantum chemical methodologies. To minimize the cavity size and to prevent water‐water hydrogen bonding loss, the water molecules adopt a shape, resembling the one found in crystal structure of gas clathrate hydrates, with water molecules tangentially oriented to the surface of hydrophobic side chain. The cage is directly hydrogen bonded to the backbone's polar groups, thus hydration shells around hydrophobic and hydrophilic groups are folded together in amphiphilic molecules. The hydrophobe enclathration implies a substantial freedom degree reduction which makes it entropically disfavored. This disadvantageous entropic contribution is partially compensated by the favorable van der Waals interactions with guest in stabilizing clathrate hydrate formation. The water shell around the side chain relates intimately with the side‐chain rotational isomerism. Present data are correlated with the experimental determined populations of the three rotamers, yielding promising results for both α‐aminobutyric acid and valine.

A molecular twist on hydrophobicity

“…Since most biomolecules are ambiphilic, there is a complex interplay between hydrophobicity and hydrophilicity in determining protein structure and function. 3 It is thought, for example, that despite the very weak nature of water/hydrophobe contacts, their vast numbers outweigh contributions from stronger interactions in the nal overall structure of biomolecules in physiological environments. 4,5 Furthermore, a popular view of the microscopic structure of water/hydrophobe mixtures calls for the formation of water cavities enclosing non-polar molecules 3,6,7 even though a high entropy investment, which is compensated by a net entropy gain produced by the liberation of solvating water molecules into the environment.…”

“…3 It is thought, for example, that despite the very weak nature of water/hydrophobe contacts, their vast numbers outweigh contributions from stronger interactions in the nal overall structure of biomolecules in physiological environments. 4,5 Furthermore, a popular view of the microscopic structure of water/hydrophobe mixtures calls for the formation of water cavities enclosing non-polar molecules 3,6,7 even though a high entropy investment, which is compensated by a net entropy gain produced by the liberation of solvating water molecules into the environment. 8,9 In his seminal review, Chandler 10 offers a more thoughtful perspective for larger hydrophobes: "But the extreme view that pictures hydrophobic solvation in terms of rigid clathrate structures, like those surrounding hydrophobic particles in gas hydrates, is clearly incorrect: intermolecular correlations in liquid matter are insufficiently strong to be consistent with this crystalline picture.…”

“…Intermolecular interactions are also quite relevant because in the current view, not repulsion, but only tiny stabilization energies are at play when hydrophobes interact with water at the molecular level. 3,4,7,25,30,31 Appropriately, in this context, statements of this sort "Of all factors driving intermolecular interactions, the hydrophobic effect is the most oen cited. At the same time, it is the least understood", 6 or "In spite of the enormous experimental and modeling efforts, many microscopic aspects related to the nature of forces and action mechanism are still not well understood" 3 are a commonplace in the scientic literature.…”

“…7 This argument ignores the contributions from secondary hydrogen interactions (those where the proton in the HB comes from a C-H bond), [32][33][34][35][36][37][38][39][40][41] and more specically, it overlooks stabilizing orbital interactions. [42][43][44][45] Recognizing present limitations, the same authors stated in a recent work 3 "there have been no signicant efforts in using modern quantum chemical methods to derive plausible forces from a true ab initio procedure". Herein, we address this specic issue and offer an in-depth study of the nature of the delicate stabilizing interactions using Natural Bond Orbitals (NBO [46][47][48][49] ), the Quantum Theory of Atoms in Molecules (QTAIM [50][51][52][53] ), and Non-Covalent Interactions (NCI [54][55][56] ) methods, analysis tools rmly rooted in the formalism of quantum mechanics.…”

Quantum Chemical Microsolvation by Automated Water Placement

“…Following a related idea, Sure et al proposed a protocol based on the analysis of the screening charge densities [ 24 ]. Another idea is to start from “idealized” solvent geometries, such as the structures of clathrates, to describe microsolvated amino acids [ 25 ]. Simm and coworkers developed a stochastic approach, where interaction surfaces of solute and solvent are identified and randomly combined.…”