Conformational Fluctuations versus Constraints in Amino Acid Side Chains: The Evolution of Information Content from Free Amino Acids to Proteins

Abstract

Like all other complex biological systems, proteins exhibit properties not found in free amino acids (i.e., emergent properties). Here, we explore top-down constraints experienced by the residue side chains in proteins compared to amino acids in increasingly complex molecular environments: free amino acids, end-capped amino acids, and the central residue in an alpha-helical nonapeptide. The crystalline structure of the contractile protein profilin Ib and the enzyme trypsin were chosen as objects of study, and submitted to 10 ns molecular dynamics (MD) simulations. The results revealed increased conformational constraints on the side chains when going from the simpler to the more complex compounds. A Shannon entropy (SE) analysis of the conformational behavior of the side chains showed in most cases a progressive and marked decrease in the SE of the chi1 and chi2 dihedral angles. This is equivalent to stating that conformational constraints on the side chain of residues increase their information content and, hence, recognition specificity compared to free amino acids. In other words, the vastly increased information content of a protein relative to its free monomers is embedded not only in the tertiary structure of the backbone, but also in the conformational behavior of the side chains. The postulated implication is that both backbone and side chains, by virtue of being conformationally constrained, contribute to the protein's recognition specificity toward other macromolecules and ligands.

Chemodiversity and Molecular Plasticity: Recognition Processes as Explored by Property Spaces

“…With regard to local flexibility, MD simulations of the protein profilin Ib performed over 10 ns revealed large differences in the behavior of the side chains compared with the free amino acids, with their conformational space severely restricted and/or shifted to regions improbable in the free state [53,54]. The significant consequences of such constraints on side-chain recognition forces and interaction fields have not been sufficiently explored and deserve to be evaluated on a larger scale [55], also because such conformational constraints can contribute notably to protein recognition specificity towards other macromolecules and ligands as proposed by Loewenstein [56].…”

Atomic Diversity, Molecular Diversity, and Chemical Diversity: The Concept of Chemodiversity

“…What this figure does not show, however, is the conformational flexibility of the side chains in the residues. Simulations performed over 10 ns revealed large differences in the behavior of the side chains in profilin Ib compared to the free amino acids, with their conformational space severely restricted and/or shifted to regions improbable in the free state [31]. The consequences of such constraints on side-chain recognition forces and interaction fields may be significant but have not been sufficiently explored [32].…”

Dispersal (Entropy) and Recognition (Information) as Foundations of Emergence and Dissolvence

“…This is a question that can be investigated at the level of components due to their probabilistic behavior [11]. In a series of computational simulations using molecular mechanics [40,41], top-down constraints experienced by the side-chains of residues in proteins compared to free amino acids were explored. The results revealed increased conformational constraints on the side-chains of residues compared to the same amino acids in monomeric (free) form.…”