Proteins achieve their functional, active, and operative three dimensional native structures by overcoming the possibility of being trapped in non-native energy minima present in the energy landscape. The enormous and intricate interactions that play an important role in protein folding also determine the stability of the proteins. The large number of stabilizing/destabilizing interactions makes proteins to be only marginally stable as compared to the other competing structures. Therefore, there are some possibilities that they become trapped in the non-native conformations and thus get misfolded. These misfolded proteins lead to several debilitating diseases. This work performs a comparative study of some existing foldability criteria in the computational design of misfold resistant protein sequences based on self-consistent mean field theory. The foldability criteria selected for this study are Ef, Δ, and Φ that are commonly used in protein design procedures to determine the most efficient foldability criterion for the design of misfolding resistant proteins. The results suggest that the foldability criterion Δ is significantly better in designing a funnel energy landscape stabilizing the target state. The results also suggest that inclusion of negative design features is important for designing misfolding resistant proteins, but more information about the non-native conformations in terms of Φ leads to worse results compared to even simple positive design. The sequences designed using Δ show better resistance to misfolding in the Monte Carlo simulations performed in the study.
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