MECHGEN · The MECHanical GENome: How DNA sequence guides chromosomal organization and dynamics

Beyond its role in encoding the primary structure of proteins, the sequence of DNA also determines its mechanical properties such as shape and flexibility. This sequence-specific mechanical code significantly influences interactions between the cellular machinery and the genome, affecting critical processes such as gene regulation and chromatin organization. However, the extent to which this MECHanical GENome drives biological function remains largely unexplored. MECHGEN seeks to bridge this gap by leveraging a recently developed coarse-graining methodology to construct a multi-resolution molecular dynamics (MD) model that integrates sequence-dependent elastic properties of DNA. This model will enable efficient simulations of genomic length DNA, chromatin, and other biologically relevant systems.Using this new methodology, we propose to study two aspects of chromosomal organization. The first will investigate how DNA sequence influences the distribution of topological strains and how sequence context determines the exposure of DNA damage in supercoiled DNA, offering new insights into genomic stability and repair mechanisms. The second line of investigation will explore how DNA sequence shapes chromatin structure and function, focusing on nucleosome positioning and higher-order chromatin architectures. By combining coarse-grained simulations with experimental data, MECHGEN aims to clarify the role of sequence variations in chromosomal organization and gene regulation. These findings could significantly impact our understanding of genomic function and stability, with potential applications in the study and treatment of genetic diseases.