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More recently, this question has witnessed a renewed interest in light of the hypothesis that knotted proteins require the assistance of non-native interactions to fold efficiently. Here, we conduct extensive equilibrium and kinetic Monte Carlo simulations of a simple off-lattice C-alpha model to explore the role of non-native interactions in the thermodynamics and kinetics of three proteins embedding a trefoil knot in their native structure. We find that equilibrium knotted conformations are stabilized by non-native interactions that are non-local, and proximal to native ones, thus enhancing them. Additionally, non-native interactions increase the knotting frequency at high temperatures, and in partially folded conformations below the transition temperatures. Although non-native interactions clearly enhance the efficiency of transition from an unfolded conformation to a partially folded knotted one, they are not required to efficiently fold a knotted protein. Indeed, a native-centric interaction potential drives the most efficient folding transition, provided that the simulation temperature is well below the transition temperature of the considered model system.<\/jats:p>","DOI":"10.1063\/5.0160886","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T10:33:36Z","timestamp":1691490816000},"update-policy":"https:\/\/doi.org\/10.1063\/aip-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Effects of sequence-dependent non-native interactions in equilibrium and kinetic folding properties of knotted proteins"],"prefix":"10.1063","volume":"159","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5476-5370","authenticated-orcid":false,"given":"Jo\u00e3o N. C.","family":"Especial","sequence":"first","affiliation":[{"name":"Departamento de F\u00edsica 1 , Faculdade de Ci\u00eancias, Ed. C8, Universidade de Lisboa, Campo Grande, Lisboa, Portugal"},{"name":"BioISI\u2014Biosystems and Integrative Sciences Institute, Faculdade de Ci\u00eancias, Universidade de Lisboa 2 , Campo Grande, Lisboa, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2493-2748","authenticated-orcid":false,"given":"Patr\u00edcia F. N.","family":"Fa\u00edsca","sequence":"additional","affiliation":[{"name":"Departamento de F\u00edsica 1 , Faculdade de Ci\u00eancias, Ed. 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