Abstract
The transmembrane domain (TMD) of membrane proteins plays an essential role in their dynamics and functions. Certain properties of TMDs, such as raft affinity and orientation, have been studied extensively both experimentally and computationally. However, the extent to which specific physicochemical properties of TMDs determine their membrane domain-partitioning thermodynamics is still far from clear. In this work, we propose an approach based on umbrella sampling molecular dynamics simulations of model membranes and idealized TMDs to quantify the effect of TMD physicochemical properties, namely, length, degree of hydrophobicity, and size of TMDs, on their membrane domain-partitioning thermodynamics. The results, which are fully consistent with previous experimental and simulation data, indicate that the concept of "hydrophobic mismatch" should go beyond differences in hydrophobic thickness to include mismatch in the degree of hydrophobicity between the TMD and the surrounding hydrocarbon lipid chains. Our method provides quantitative insights into the role of specific physicochemical features of TMDs in membrane localization and orientation, which will be broadly useful for predicting the raft affinity and membrane partitioning of any transmembrane protein.