Force-field Dependency of Leu-rich Helical Peptides Dimerization Energy in Lipid Bilayers. I. United-atom Simulations Show Discrepancy from Experiments and All-atom Simulations

United-atom (UA) description of aliphatic carbon-hydrogen atoms with single particles have been used in simulation analyses of protein/lipid systems.However, UA force fields (FFs) simulations have shown inaccuracy in transmembrane (TM) helical peptides dimerization dynamics within lipid membranes.For example, the self-dimerized state of a TM helical peptide (AALALAA)3 in a phospholipid bilayer is unrealistically unstable in simulations under two FFs, namely, the OPLS-all atom (AA) protein/Berger UA lipids and GROMOS 53A6 (Gr 53a6 ) FFs, whereas AA Charmm36 (Ch 36AA ) FF showed a dimerization energy comparable with the experiment.Here we show that the dimer stability of a Lys-flanked poly-Leu peptide (KL22) exhibits no or little dimerization propensity with Gr 53a6 , but shows dimerization propensity of the free energy of -7.5 kJ/mol with Ch 36AA comparable to the experiment (-8.3 kJ/mol).A peptide comprised solely of Leu (L21) showed similar FFdependency.Although the dimer stability was fairly similar between Ch 36AA and Gr 53a6 for both poly-Ile and poly-Val helices, a Ch 36AA >Gr 53a6 stability difference was also seen for poly-Ala helices.While the UA parameters have normally been adjusted guided by the experiments with simple systems using the amino acid side chain analogues, the findings presented here highlight limited transferability of UA parameters to the settings of peptides/lipid membranes.