Three-dimensional (3D) maps of the
hydropathic environments of
protein amino acid residues are information-rich descriptors of preferred
conformations, interaction types and energetics, and solvent accessibility.
The interactions made by each residue are the primary factor for rotamer
selection and the secondary, tertiary, and even quaternary protein
structure. Our evolving basis set of environmental data for each residue
type can be used to understand the protein structure. This work focuses
on the aromatic residues phenylalanine, tyrosine, and tryptophan and
their structural roles. We calculated and analyzed side chain-to-environment
3D maps for over 70,000 residues of these three types that reveal,
with respect to hydrophobic and polar interactions, the environment
around each. After binning with backbone ϕ/ψ and side
chain χ1, we clustered each bin by 3D similarities
between map–map pairs. For each of the three residue types,
four bins were examined in detail: one in the β-pleat, two in
the right-hand α-helix, and one in the left-hand α-helix
regions of the Ramachandran plot. For high degrees of side chain burial,
encapsulation of the side chain by hydrophobic interactions is ubiquitous.
The more solvent-exposed side chains are more likely to be involved
in polar interactions with their environments. Evidence for π–π
interactions was observed in about half of the residues surveyed [phenylalanine
(PHE): 53.3%, tyrosine (TYR): 34.1%, and tryptophan (TRP): 55.7%],
but on an energy basis, this contributed to only ∼4% of the
total. Evidence for π–cation interactions was observed
in 14.1% of PHE, 8.3% of TYR, and 26.8% of TRP residues, but on an
energy basis, this contributed to only ∼1%. This recognition
of even these subtle interactions in the 3D hydropathic environment
maps is key support for our interaction homology paradigm of protein
structure elucidation and possibly prediction.
Mechanosensitive channels respond to mechanical forces exerted on the cell membrane and play vital roles in regulating the chemical equilibrium within cells and their environment. High-resolution structural information is required to understand the gating mechanisms of mechanosensitive channels. Protein-lipid interactions are essential for the structural and functional integrity of mechanosensitive channels, but detergents cannot maintain the crucial native lipid environment for purified mechanosensitive channels. Recently, detergent-free systems have emerged as alternatives for membrane protein structural biology. This report shows that while membrane-active polymer, SMA2000, could retain some native cell membrane lipids on the transmembrane domain of the mechanosensitive-like YnaI channel, the complete structure of the transmembrane domain of YnaI was not resolved. This reveals a significant limitation of SMA2000 or similar membrane-active copolymers. This limitation may come from the heterogeneity of the polymers and nonspecific interactions between the polymers and the relatively large hydrophobic pockets within the transmembrane domain of YnaI. However, this limitation offers development opportunities for detergent-free technology for challenging membrane proteins.
Atomic-resolution protein structural models are prerequisites for many downstream activities like structure-function studies or structure-based drug discovery. Unfortunately, this data is often unavailable for some of the most interesting and therapeutically important proteins. Thus, computational tools for building native-like structural models from less-than-ideal experimental data are needed. To this end, interaction homology exploits the character, strength and loci of the sets of interactions that define a structure. Each residue type has its own limited set of backbone angle-dependent interaction motifs, as defined by their environments. In this work, we characterize the interactions of serine, cysteine and S-bridged cysteine in terms of 3D hydropathic environment maps. As a result, we explore several intriguing questions. Are the environments different between the isosteric serine and cysteine residues? Do some environments promote the formation of cystine S–S bonds? With the increasing availability of structural data for water-insoluble membrane proteins, are there environmental differences for these residues between soluble and membrane proteins? The environments surrounding serine and cysteine residues are dramatically different: serine residues are about 50% solvent exposed, while cysteines are only 10% exposed; the latter are more involved in hydrophobic interactions although there are backbone angle-dependent differences. Our analysis suggests that one driving force for –S–S– bond formation is a rather substantial increase in burial and hydrophobic interactions in cystines. Serine and cysteine become less and more, respectively, solvent-exposed in membrane proteins. 3D hydropathic environment maps are an evolving structure analysis tool showing promise as elements in a new protein structure prediction paradigm.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.