Intrahelical ion pairing interactions: Exploring charged amino acid side chain length
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Proteins are essential parts of organisms and participate in every process within cells. All proteins are built from different combinations of twenty different L-α-amino acids. These amino acids feature different side chain lengths and functionalities. The role of the side chain length in protein function and structure is poorly understood. As a first step, the role of side chain lengths of charged amino acids in intrahelical ion pairing interactions is investigated by studies on model α-helical peptides, corroborated with molecular modeling and surveys on natural proteins. The role of position dependence in short model peptides on the helix propensity of amino acids is first investigated to establish the foundation for using statistical mechanical models based on Lifson-Roig theory. Based on these results, the helix propensity of Ala is lower than previously published values in analogous Ala-based peptides. Position independent helix propensities were observed for Leu, Phe, and Pff, except for Leu at position 16. The unique behavior of Leu16 may be due to capping effects or adoption of a 3 10 -helix. The role of side chain length of amino acids in helix stabilizing ion pairing interactions was studied. Lys forms robust helix stabilizing interactions with Glu in the Glu-Lys ( i, i + 4 ) placement. However, decreasing the side chain length by one methylene results in a pH dependent interaction that lacks robustness. Interestingly, the robustness is also lost when Glu is replaced by Asp (one methylene shorter). Increasing the side chain length of Glu to Aad does not result in any appreciable helix stabilization. Hence, Nature may have selected Glu to form durable interactions with Lys while Asp may have been selected for its ability to form strong environment dependent interactions with Lys. The relevance of this study was corroborated by a survey on sequence patterns in protein helices.