Thermodynamic landscapes of amino acid solvation within lipid bilayers: A comprehensive molecular dynamics study

Abstract

The interaction of amino acids with lipid bilayers dictates fundamental aspects of membrane protein folding, stability, and function. Quantifying the thermodynamics of amino acid solvation within the heterogeneous membrane environment remains a key challenge. Using extensive all-atom molecular dynamics simulations (>15 μs total) and enhanced sampling techniques, we calculated the potential of mean force profiles for all standard amino acids partitioning into a 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer, considering both neutral and charged states of ionizable residues. The resulting free energy landscapes consistently show substantial barriers (>5–60 kJ/mol) for penetrating the hydrophobic core, highlighting the importance of backbone polarity. Most amino acids exhibit preferential stabilization at the membrane interface, driven by a balance of hydrophobic and polar interactions. Charged residues face the largest core penalties but can be stabilized near headgroups via electrostatic interactions and local membrane adaptation. Comparisons with diverse experimental scales confirm qualitative trends but underscore quantitative differences arising from backbone effects and environmental context. This comprehensive dataset provides a basis for the construction of more complex molecular structures using amino acids as building blocks.