Conformoreplication and the Conformotype: Formalising Alt-F Proteins as a Conceptual Extension of the Central Dogma and a Third Tier of Molecular Inheritance

Protein conformational inheritance is documented across bacteria, fungi, and neurons, and while several authors have argued for its conceptual inclusion in molecular inheritance frameworks, a concise, widely adopted formal vocabulary that unifies these literatures remains lacking. Naming by pathological outcome rather than mechanism has partitioned prion disease research, adaptive conformational biology, and protein engineering into separate silos despite a shared mechanistic basis. This review formalises the shared mechanism with three terms. Alt-F protein (alternatively folded protein) names the mechanistic class irrespective of outcome. Conformoreplication names the protein-to-protein templated propagation of fold geometry — a third conceptual extension of the Central Dogma. The conformotype is the third molecular inheritance tier, transmitted through cell division independently of DNA sequence or epigenetic marks, initiated by post-translational modifications acting as environmental transducers, and regulated by the chaperone network. The framework identifies blind spots in three research fields that the current sequence-centric paradigm structurally excludes: AMR surveillance that cannot detect conformationally-encoded resistance in genotypically susceptible isolates; industrial biotechnology that screens enzyme variants by sequence but not conformational state; and neurodegeneration therapeutics that targets downstream aggregates rather than the upstream chaperone regulatory failure. To move beyond conceptual identification of these blind spots, the review operationalises each through a concrete analytical pipeline — integrating conformational proteomics, MSA-subsampled AlphaFold screening, and chaperone modulation assays — demonstrating that the conformotype framework is not merely taxonomic but immediately actionable across all three fields.