Abstract 3720: Histone dynamics and minor groove width: structural drivers of mutations in <i>KRAS</i> and <i>NRAS</i>

Abstract Introduction: Cancer development is driven by genetic mutations, particularly in genomic hotspots, which are sequences prone to mutations. This study seeks to understand the structural properties of DNA in these regions, focusing on the minor groove width (MGW), helical parameters (ProT, HelT, roll, EP), and DNA-histone interactions. Methods and Materials: An expanded hotspot database was developed by including additional information about mutation-associated sequences and structural properties. A control group of random exon sequences was established to serve as a baseline for analysis. Structural differences were assessed using statistical tests to quantify clustering of hotspot sequences with higher mutation counts around specific MGW values. The KRAS and NRAS genes were selected for molecular dynamics simulations due to their role in oncogenesis. Several simulations were conducted: one each for both the normal KRAS and NRAS sequences and others representing the most common mutations. The simulations, lasting 100 ns each and using the AMBER99SB-ILDN force field. Results and Discussion: The average minor groove width (MGW) values observed in the hotspots revealed structural differences that may impact stability. The normal KRAS and NRAS sequences exhibited a narrower MGW of 5.4 Å, while sequences with common mutations displayed wider MGW values. This variation in MGW may influence stability. Molecular dynamics simulations indicated that the normal KRAS and NRAS sequences exhibited greater fluctuations compared to its mutated counterparts. The root mean square fluctuation (RMSF) showed that the normal sequence had higher fluctuations around the guanine-containing regions in KRAS or the adenine-containing region in NRAS. This instability may be linked to the enhanced mutation rates observed in KRAS and NRAS hotspot regions. Figures illustrating RMSF plots of KRAS demonstrated that the normal sequence’s interaction with histone proteins was more unstable than that of sequences with common mutations. The presence of guanine appears to introduce significant strain in the DNA-histone interaction, further correlating with the narrower MGW values. This strain may lead to increased mutational frequency, contributing to the oncogenic potential of KRAS mutations. For NRAS, the introduction of the adenine nucleotide contributed to the instability of the DNA-histone interaction, particularly when the DNA curved closer to the histone. Conclusion: The simulations provide valuable insights into the dynamics of the KRAS and NRAS gene, revealing how specific mutations affect DNA stability and interaction with histones. By focusing on the structural factors that predispose certain regions to mutations, this research contributes to a greater understanding of cancer biology. Citation Format: Yisrael Wiener, Isaac Silverman, Sanjay Goel, Radhashree Maitra. Histone dynamics and minor groove width: structural drivers of mutations in KRAS and NRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3720.