Multiscale Coarse-Graining of the Protein Energy Landscape

A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states.Author Summary: Biological function originates from the dynamical motions of proteins in response to cellular stimuli. Protein dynamics arise from physical interactions that are well-predicted by detailed atomistic simulations. In order to examine large protein complexes on long timescales of biological importance, however, coarse-grained simulation approaches are needed to complement experiment. Previous coarse-grained models have proved successful for investigations involving a given protein's native structure, including protein folding and structure prediction. We construct a model capable of simulating proteins regardless of their sequence or structure. The present coarse-grained model was, however, developed rigorously from the underlying atomistic forces as opposed to knowledge-based or ad hoc parameterizations. Examination of the model predictions on various accessible timescales reveals successes and limitations of the model. While functionally relevant conformational transitions can be studied, the coarse-grained representation has some difficulty with the ab initio folding of the peptide chain into its proper structure. Our observations highlight the complex molecular nature of a protein's underlying energy landscape, offering rigorous insight into the information missing in reduced representations of the peptide chain. With these caveats in mind, the physical interaction–based, coarse-grained model will find application in simulations of a wide variety of proteins and continue to guide future coarse-graining efforts.