On the Automatic Optimization of Lipid Models in the Martini Force Field using SwarmCG

Abstract

After two decades of continued development of the Martini coarse-grained force field (CG FF), further refining the already rather accurate Martini lipid models has become a demanding task that could benefit from integrative data-driven methods. Automatic approaches are increasingly used in the development of accurate molecular models, but they typically make use of specifically-designed interaction potentials that transfer poorly to molecular systems or conditions different than those used for model calibration. As a proof of concept here we employ SwarmCG, an automatic multi-objective optimization approach facilitating the development of lipid force fields, to refine specifically the bonded interaction parameters in building blocks of lipid models within the framework of the general Martini CG FF. As targets of the optimization procedure, we employ both experimental observables (top-down references: area per lipid & bilayer thickness) and all-atom molecular dynamics simulations (bottom-up reference), respectively informing on the supra-molecular structure of the lipid bilayer systems and on their sub-molecular dynamics. In our training sets we simulate at different temperatures in the liquid and gel phases up to 11 homogeneous lamellar bilayers, composed of phosphatidylcholine lipids spanning various tail lengths and degrees of (un)saturation. We explore different CG representations of the molecules and evaluate improvements a posteriori using additional simulation temperatures and a portion of the phase diagram of a DOPC/DPPC mixture. Successfully optimizing up to ~80 model parameters within still limited computational budgets, we show that this protocol allows to obtain improved transferable Martini lipid models. In particular, the results of this study demonstrate how a fine tuning of the representation and parameters of the models may improve their accuracy, and how automatic approaches such as SwarmCG may be very useful to this end.

Martini 3 Coarse-Grained Force Field for Cholesterol

“…When replacing DLiPC with the more saturated DOPC, phase separation becomes substantially less clear, with more mixing between DOPC and DPPC as well as a decrease in the enrichment of cholesterol–DPPC contacts (Figure b,d,f,h,i,j). No clear phase separation is observed at either 290 or 300 K. Experimental data point out that a single uniform phase should be obtained for DPPC/DOPC/CHOL at 300 K, , but coexistence of Lo and Ld phases should be observed at 290 K. , It is not clear how much our cholesterol model is impacting phase separation in this ternary model and whether there is much room for improvement, especially because the underlying DOPC/DPPC and POPC/DPPC binary mixtures also fail to show correct phase separation with the current Martini 3 lipid model . If we compare the specific contact fractions calculated from the both Martini 3 and 2 systems (Figure i,j), we already observe a small improvement in the enrichment of DPPC–DPPC and DPPC–CHOL contacts with the newer model.…”

“…These results hint at a slightly improved propensity to phase separate. Further developments focused on the lipid models will likely fix these ternary models by improving the underlying DPPC/DOPC binary mixtures . Moreover, it is worth noting that these results were obtained without the temperature differences arising from LINCS convergence and influencing the degree of phase separation .…”

Martini 3 Coarse-Grained Force Field for cholesterol

“…No clear phase separation is observed at either 290 or 300 K. Experimental data points out that a single uniform phase should be obtained for DPPC:DOPC:CHOL at 300 K 119,126 , but coexistence of Lo and Ld phases should be observed at 290 K 119,126 . It is not clear how much our cholesterol model is impacting phase separation in this ternary model and whether there is much room for improvement, especially since the underlying DOPC:DPPC and POPC:DPPC binary mixtures also fail to show correct phase separation with the current Martini 3 lipid model 127 . If we compare the specific contact fractions calculated from the both Martini 3 and 2 systems (Figure 5 i,j), we already observe a small improvement in the enrichment of DPPC-DPPC and DPPC-CHOL contacts with the newer model.…”

Martini 3 Coarse-Grained Force Field for cholesterol

“…No clear phase separation is observed at either 290 or 300 K. Experimental data points out that a single uniform phase should be obtained for DPPC:DOPC:CHOL at 300 K 116,123 , but coexistence of Lo and Ld phases should be observed at 290 K 116,123 . It is not clear how much our cholesterol model is impacting phase separation in this ternary model and whether there is much room for improvement, especially since the underlying DOPC:DPPC and POPC:DPPC binary mixtures also fail to show correct phase separation with the current Martini 3 lipid model 124 . If we compare the specific contact fractions calculated from the both Martini 3 and 2 systems (Figure 5 i,j), we already observe a small improvement in the enrichment of DPPC-DPPC and DPPC-CHOL contacts with the newer model.…”

“…These results hint at a slightly improved propensity to phase separate. Further developments focused on the lipid models will likely fix these ternary models, by improving the underlying DPPC:DOPC binary mixtures 124 . Moreover, it is worth noting that these results were obtained without the temperature differences arising from LINCS convergence and influencing the degree of phase separation 55 .…”