Constrained Evolutionary Design of Matrixyl Analogs: Balancing Permeability and Functional Preservation Through Computational Optimization

Matrixyl (palmitoyl pentapeptide-4, KTTKS core) is a collagen-stimulating peptide used in topical anti-ageing products, but its in-use efficacy is limited by poor permeation through the stratum corneum. We describe a deterministic computational workflow that combines a tournament genetic algorithm and NSGA-II with exact RDKit molecular descriptors to search the fixed-length, edit-distance-2 neighbourhood of KTTKS (3,706 candidate sequences) for analogs with descriptors more favourable for passive transdermal diffusion. The search returns a 9-member Pareto frontier that quantifies the trade-off between predicted permeability and motif preservation. Five of the nine frontier members carry the same substitution, lysine to proline at position 4 (K4P). This single change lowers the topological polar surface area by 25.6%, removes the +1 charge contributed by lysine, and reduces the functional-preservation score from 1.00 (KTTKS) to 0.67. The frontier ranking is unchanged by {+/-}30% perturbations to the TPSA and Mw penalty weights and by a 30% increase in the LogP penalty; only a 30% reduction in the LogP penalty produces rank movement. The frontier matches the ground-truth Pareto set obtained by exhaustive enumeration of all 3,706 candidates (precision and recall both 100%). On the basis of these results we recommend three sequences for experimental validation: PTTPS (largest predicted gain), KTTPS (single-mutation, conservative), and KTTPP (backup). All code, results, and figures are released under MIT and CC BY 4.0.