MutSα's Multi-Domain Allosteric Response to Three DNA Damage Types Revealed by Machine Learning

Frontiers in Physics

Gmeiner, William H.¹  Thompson, William G.²  Melvin, Ryan L.²  Godwin, Ryan C.²  Salsbury, Freddie R. Jr.² 

[1] Gmeiner Laboratory, Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA;Salsbury Group, Department of Physics, Wake Forest University, Winston-Salem, NC, USA

关键词: machine learning;    Allosteric Regulation;    Molecular Dynamics Simulation;    DNA Repair Enzymes;    DNA Damage;   

DOI  :  10.3389/fphy.2017.00010

学科分类：物理（综合）

来源: Frontiers

【 摘 要 】

MutSalpha is a key component in the mismatch repair (MMR) pathway. This protein is responsible for initiating the signaling pathways for DNA repair or cell death. Herein we investigate this heterodimer’s post-recognition, post-binding response to three types of DNA damage involving cytotoxic, anti-cancer agents – carboplatin, cisplatin, and FdU. Through a combination of supervised and unsupervised machine learning techniques along with more traditional structural and kinetic analysis applied to all-atom molecular dynamics (MD) calculations, we predict that MutSalpha has a distinct response to each of the three damage types. Via a binary classification tree (a supervised machine learning technique), we identify key hydrogen bond motifs unique to each type of damage and suggest residues for experimental mutation studies. Through a combination of a recently developed clustering (unsupervised learning) algorithm, RMSF calculations, PCA, and correlated motions we predict that each type of damage causes MutS↵to explore a specific region of conformation space. Detailed analysis suggests a short range effect for carboplatin – primarily altering the structures and kinetics of residues within 10 angstroms of the damaged DNA – and distinct longer-range effects for cisplatin and FdU. In our simulations, we also observe that a key phenylalanine residue – known to stack with a mismatched or unmatched bases in MMR – stacks with the base complementary to the damaged base in 88.61% of MD frames containing carboplatinated DNA. Similarly, this Phe71 stacks with the base complementary to damage in 91.73% of frames with cisplatinated DNA. This residue, however, stacks with the damaged base itself in 62.18% of trajectory frames with FdU-substituted DNA and has no stacking interaction at all in 30.72% of these frames. Each drug investigated here induces a unique perturbation in the MutS↵complex, indicating the possibility of a distinct signaling event and specific repair or death pathway (or set of pathways) for a given type of damage.

【 授权许可】

CC BY