Electronic properties of amino acid side chains: quantum mechanics calculation of substituent effects

These studies revealed that: (1) different semiempirical QM methods yield similar results for the electronic effects of side chain groups, (2) polarizability, which reflects molecular deformability, represents steric factors in electronic terms, and (3) inductive effects contribute to the propensity of an amino acid for α-helices.The data provide initial characterization of the substituent effects of amino acid side chains and suggest that these properties affect electron density along the peptide backbone.How the amino acid sequence of a protein determines its native tertiary structure is one of the most perplexing questions in biology. The formation of secondary structure (α-helices, β-strands and coils/turns) is an intermediate step in this process, although, in some cases, this may occur very late in folding just prior to consolidation of the final 3-D structure [1-4]. Hydrophobicity and steric effects are two major factors that govern protein folding [5-7]. In addition, I [8] have recently suggested that electronic properties of amino acids, including inductive effects, may contribute to the propensity for secondary structure. This possibility merits further investigation especially in view of several recent findings. First, although the hydrophobicity of an amino acid correlates with preference for β-strand and coil conformations, it does not predict tendency to form α-helices [8]. This suggests that adoption of β-strands vs. α-helices may be driven by different molecular forces. Second, electronic effects have provided important insights into structural preferences and have dramatically revised our thinking about the factors that impact rotation about a single bond. For example, the fact that ethane prefers the staggered conformation over the eclipsed conformation has long been ascribed to steric factors [9]. However, Pophristic and Goodman [10] demonstrated that hyperconjugative effects (electron delocalization into antibonding orbitals) rather than steric e