Coarse-grained molecular dynamics simulations of base-pair mismatch recognition protein MutS sliding along DNA

Area of Science:

• Molecular Biology
• Genetics
• Biophysics

Background:

• DNA mismatches arise from replication errors and environmental factors, necessitating correction by the mismatch repair (MMR) pathway to maintain genome integrity.
• In Escherichia coli (E. coli), the MutS protein initiates MMR by locating base-pair mismatches along the DNA.
• Conformational changes in MutS, triggered by ADP/ATP exchange, influence its DNA-sliding dynamics, which are crucial for mismatch searching but remain incompletely understood.

Purpose of the Study:

• To investigate the detailed structural dynamics of E. coli MutS during DNA sliding in different conformational states (ADP-bound, ATP-bound open clamp, ATP-bound closed clamp).
• To elucidate how these distinct MutS conformations affect its diffusion mechanisms and mismatch searching efficiency.

Main Methods:

• Coarse-grained molecular dynamics simulations were employed to model E. coli MutS bound to DNA.
• Simulations were conducted for three MutS conformations: MutS^ADP, ATP-bound open clamp ($$), and ATP-bound closed clamp ($$).

Main Results:

• Observed conformation-dependent diffusion of MutS along DNA.
• MutS^ADP and the open clamp conformation ($$) exhibited rotation-coupled diffusion.
• Groove-crossing events, where MutS temporarily diffused in a rotation-uncoupled manner, were observed more frequently for the open clamp conformation ($$).
• The open clamp conformation ($$) showed inefficient mismatch checking despite faster diffusion and broader reach.

Conclusions:

• The study clarifies the distinct DNA-sliding mechanisms of E. coli MutS based on its bound nucleotide (ADP vs. ATP).
• Different MutS conformations exhibit unique diffusion patterns (rotation-coupled vs. uncoupled) and groove-crossing behaviors.
• While ATP-bound MutS diffuses more rapidly, its conformational flexibility may compromise the efficiency of mismatch detection compared to ADP-bound MutS.