Abstract
Aspartic acid, glutamic acid and histidine are ionizable residues occupying various protein environments and perform many different functions in structures. Their roles are tied to their acid/base equilibria, solvent exposure, and backbone conformations. We propose that the number of unique environments for ASP, GLU and HIS is quite limited. We generated maps of these residue's environments using a hydropathic scoring function to record the type and magnitude of interactions for each residue in a 2703-protein structural dataset. These maps are backbone-dependent and suggest the existence of new structural motifs for each residue type. Additionally, we developed an algorithm for tuning these maps to any pH, a potentially useful element for protein design and structure building. Here, we elucidate the complex interplay between secondary structure, relative solvent accessibility, and residue ionization states: the degree of protonation for ionizable residues increases with solvent accessibility, which in turn is notably dependent on backbone structure.
Highlights
Proteins are largely composed of unique combinations of 20 possible amino acids, varying from tens to thousands of residues in length
Our model suggests ASP141A has an elevated pKa and, when protonated, forms a hydrogen bond with ASP215A
From above and our previous reports (Ahmed et al, 2015; Ahmed et al, 2019), it is clear that the hydropathic environment surrounding an amino acid residue in a protein can be mapped in terms of its interactions
Summary
Proteins are largely composed of unique combinations of 20 possible amino acids, varying from tens to thousands of residues in length. Specific protein sequences organize themselves into unique and well-defined secondary structures that comprise much larger and more complex structures that determine their functions. This relationship between structure and function is important to grasp in order to understand how different features of biological targets can be exploited for treatments of various disease states. One important aspect of this relationship is the dependence of protein structure on pH and protonation states of constituent residues. Histidine (HIS), for example, has a nominal pKa of 6.00 (Hunt, 2021), situated closely enough to physiological pH that its imidazole sidechain can act either as a cationic dual hydrogen bond donor or a neutral donor and acceptor depending on its local pH pH Tuning of Protein Hydropathic Environments environment. The pH-dependence of protein function is a well-established principle and has promoted extensive research into identifying optimum pH for activity of various other macromolecules (Talley and Alexov, 2010)
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