3D interaction homology: Hydropathic interaction environments of serine and cysteine are strikingly different and their roles adapt in membrane proteins

Abstract

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.

Systematized analysis of secondary structure dependence of key structural features of residues in soluble and membrane-bound proteins

“…Additionally, all residues, apart from glycine and proline, exhibit their highest solvent accessibility in the left-hand α-helix region. These observations were anticipated, as we have seen them previously ( Ahmed et al, 2015 , Ahmed et al, 2019 , AL Mughram et al, 2021 , Catalano et al, 2021 ), and they are consistent with literature observations of SASA with respect to secondary structure ( Lins et al 2003 ).

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“…We believe that the relative solvent accessibility and the hydropathic natures of residues found in both types of proteins are secondary structure-dependent and shed light on an important relationship between structure and protein folding in polar and hydrophobic environments. This work supplements findings of our previous contributions studying the hydropathic environments of specific amino acid types ( Ahmed et al, 2015 , Ahmed et al, 2019 , AL Mughram et al, 2021 , Catalano et al, 2021 , Herrington and Kellogg, 2021 ), by encompassing all residue types in the context of soluble and membrane protein environments. As a result, we highlight notable differences in residue populations, SASAs and interaction characters between both.…”

“…Our two datasets are as follows: 2703 soluble proteins described earlier ( Ahmed et al, 2015 ) and 369 membrane protein structures extracted ( Catalano et al, 2021 ) from the MemProtMD database ( Newport et al, 2019 ). This set includes an artificial lipid molecule (dipalmytoylphosphatidylcholine, DPPC) to simulate the (not structurally-characterized) membrane.…”

“…The recent AlphaFold program ( Jumper et al, 2021 ) and implementations of Baker’s Rosetta ( Yang et al, 2020 ) are particularly noteworthy. Our approach has focused on characterizing and cataloguing those inter-atomic interactions and other structural characteristics as a function of secondary structure in three-dimensional maps ( Ahmed et al, 2015 , Ahmed et al, 2019 , AL Mughram et al, 2021 , Catalano et al, 2021 , Herrington and Kellogg, 2021 ).…”

Table4.pdf

“…Recently, in our report on phenylalanine, tryptophan, and tyrosine, we showed that the subtle effects of π-π and π-cation interactions are encoded in their 3D hydropathic interaction maps (AL Mughram et al, 2021). In a report on serine and cysteine we highlight the major structural features-similarities and differences-between these two isosteric residues (Catalano et al, 2021). Importantly, our analyses describe residues by cataloguing their environments in terms of interactions and not identity.…”