3D interaction homology: The hydrophobic residues alanine, isoleucine, leucine, proline and valine play different structural roles in soluble and membrane proteins

Abstract

The aliphatic hydrophobic amino acid residues—alanine, isoleucine, leucine, proline and valine—are among the most common found in proteins. Their structural role in proteins is seemingly obvious: engage in hydrophobic interactions to stabilize secondary, and to a lesser extent, tertiary and quaternary structure. However, favorable hydrophobic interactions involving the sidechains of these residue types are generally less significant than the unfavorable set arising from interactions with polar atoms. Importantly, the constellation of interactions between residue sidechains and their environments can be recorded as three-dimensional maps that, in turn, can be clustered. The clustered average map sets compose a library of interaction profiles encoding interaction strengths, interaction types and the optimal 3D position for the interacting partners. This library is backbone angle-dependent and suggests solvent and lipid accessibility for each unique interaction profile. In this work, in addition to analysis of soluble proteins, a large set of membrane proteins that contained optimized artificial lipids were evaluated by parsing the structures into three distinct components: soluble extramembrane domain, lipid facing transmembrane domain, core transmembrane domain. The aliphatic residues were extracted from each of these sets and passed through our calculation protocol. Notable observations include: the roles of aliphatic residues in soluble proteins and in the membrane protein’s soluble domains are nearly identical, although the latter are slightly more solvent accessible; by comparing maps calculated with sidechain-lipid interactions to maps ignoring those interactions, the potential extent of residue-lipid and residue-interactions can be assessed and likely exploited in structure prediction and modeling; amongst these residue types, the levels of lipid engagement show isoleucine as the most engaged, while the other residues are largely interacting with neighboring helical residues.

Studying Conformational Properties of Transmembrane Domain of KCNE3 in a Lipid Bilayer Membrane Using Molecular Dynamics Simulations

“…The association of the KCNE3 TMD with lipid bilayers in the presence of mutations is also similar to that of the wild-type KCNE3. This behavior might be due to the fact that the interaction impairing mutations contain hydrophobic amino acid alanine and may favorably interact with the lipid acyl chain [38]. The interaction and dynamics properties of Nand C-termini of KCNE3 with lipid bilayers are variable with stability flexible dynamics in the presence of different interaction-impairing mutations when compared to that of the wild-type KCNE3.…”

HINT, a code for understanding the interaction between biomolecules: a tribute to Donald J. Abraham

“…The interaction types are color-coded by type: green- favorable hydrophobic interactions, i.e., depicting hydrophobic interactions between the residue depicted and other atoms in its environment; purple- unfavorable hydrophobic (i.e., hydrophobic-polar) interactions; blue- favorable polar (e.g., hydrogen bonding) interactions; and red- unfavorable polar interactions. For more explanation, see the following: alanine- Ahmed et al (2019 ), isoleucine- AL Mughram et al (2023 ), serine and cysteine- Catalano et al (2021 ), phenylalanine- AL Mughram et al (2023 ), aspartic acid- Herrington and Kellogg (2021 ).…”

“…While our first goal was to document the interactions in which these residues engage, we were also able to develop an improved understanding of their roles in protein structure: 1) serine is considered to be somewhat more polar than cysteine but is significantly more solvent exposed; 2) while both have similarly consistent interaction roles (∼50–60% favorable polar, Figure 8 ) regardless of their accessibility, clearly very few cysteines are found on the outside of proteins; 3) it is also interesting ( Figure 8 ) that bridging (-S–S- bonded) cysteines exist in much more hydrophobic environments than their unbridged analogs, which may be mechanistically suggestive. In another more recent study, the aliphatic hydrophobic residues were examined in both soluble and membrane proteins ( AL Mughram et al, 2023 ), which surprisingly revealed somewhat modest differences in interaction profiles for these residues in soluble proteins, where they are often buried, and membrane proteins, where they are exposed to lipids. The latter is particularly important because very few X-ray crystal or even cryo-EM structures of membrane proteins retain their native lipids ( Guo, 2020 ).…”

13Cβ‐Valine and 13Cγ‐Leucine Methine Labeling To Probe Protein Ligand Interaction

“…In the case of solventexposed surface amino acids Leu or Val are represented to a lesser extent, but if present have a high probability to interact with a molecular binding partner. [37][38] Secondly, therapeutically active compounds frequently feature aromatic systems. Recent statistical analysis of physicochemical and structural properties reveal that 76 % of drugs approved within the last decade feature one or more heteroaromatic ring structures.…”