Molecular Insights into Distinct Membrane-insertion Behaviors and Mechanisms of 20 Amino Acids: an All-atom MD Simulation Study

I nterfacial interactions of proteins with cell membranes play important roles in fundamental physiological processes of cells. The binding of proteins to membranes involves interactions between amino acids and membranes. However, the mechanism underlying amino acids’ membrane behavior remains elusive. Herein, all-atom molecular dynamic simulations were applied to comprehensively investigating the molecular details of interactions between 20 amino acids with DOPC membranes. Our results show that 20 amino acids exhibit distinct membrane insertion activities, which are not simply determined by the side chain properties of amino acids. Aromatic Tyr/Phe/Trp, hydrophobic Val/Ile/Leu/Met, positively-charged Arg and hydrophilic Cys exhibit significantly strong membrane insertion capacities with different characteristic insertion depths and insertion angles. Surprisingly, hydrophobic Ala, positively-charged His/Lys, hydrophilic Asn/Ser/Gln/Thr, negatively-charged Asp/Glu and Pro/Gly have low membrane insertion capabilities. Considering the chemical structures and interaction details of amino acids with membranes, we suggest that the abundance and diversity of interaction sites and types, the synergistic effect of hydrophilic and hydrophobic interactions of amino acids with membranes and the structural flexibility of amino acids are key factors for determining membrane insertion capabilities and characteristics of amino acids. Our study sheds light on the atomic mechanism of interactions between single amino acids and membranes.