Abstract B031: Advanced therapeutic analysis of undruggable oncoprotein KRAS; 3D structural and functional significance by I-TASSER

Abstract We employed the critical assessment of structure and function of protein (CASP) winner i-TASSER (Iterative Threading Assembly Refinement) bioinformatic tool to predict the full-length 3D structure and thermodynamic states of the KRAS-Human protein (PDB ID: 7X8N). The primary amino acid sequence is extended by LOMETS for template identification, followed by assembly through SPICKER clustering based on energy state minimization. Further, structural refinement and visualization were performed by Nanoscale Molecular Dynamics and Visual Molecular Dynamics. 5 different thermodynamic state models were generated with confidence scores (C-scores) ranging from -0.02 to -1.45 and cluster densities (CD) between 0.0683 and 0.2835. The Ramachandran plot analysis confirmed left-handed beta-sheet conformations. The B-factor values were calculated to assess thermal mobility and structural stability, showing lower values in beta strands, indicating enhanced stability. Solvent accessibility scores ranged from 0 (buried) to 9 (highly exposed), highlighting potential ligand-binding regions crucial for molecular targets. This model exposed (6-9), (18-23), (77-83), (109-116), 139, (141-146), (159-160), (155-156), and 188 amino acid pairs seemed most vulnerable with a solvent accessibility score of “0.” Statistical analyses, including ANOVA on C-score and cluster density significant differences (P < 0.005) and regression analyses, indicated that solvent accessibility and structural stability metrics follow normal distributions, with an R2 of 0.60. This integrated computational approach delineates stable KRAS conformations and mutational hotspots, providing a foundation for targeted drug discovery by elucidating key structural features that regulate oncogene signaling pathways. Citation Format: SDanish Kadir, Noushad Javed. Advanced therapeutic analysis of undruggable oncoprotein KRAS; 3D structural and functional significance by I-TASSER [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr B031.