Effects of Nucleotide and End-Dependent Actin Conformations on Polymerization

Area of Science:

• Cellular biology
• Biophysics
• Molecular dynamics

Background:

• Actin cytoskeleton regulation is crucial for cellular functions.
• Actin-binding proteins and nucleotide state influence actin filament dynamics.
• Understanding actin monomer conformation is key to polymerization control.

Purpose of the Study:

• To investigate the conformational differences between ATP- and ADP-bound actin monomers.
• To analyze the structural impact of nucleotide state on actin filament ends.
• To elucidate the molecular mechanisms governing actin polymerization rates.

Main Methods:

• Extended molecular dynamics simulations of actin monomers and filaments.
• Analysis of actin monomer twist and conformation in different nucleotide states.
• Comparison of simulated filament end structures with G-actin crystal structures.

Main Results:

• Both ATP- and ADP-actin monomers exhibit reduced twist compared to crystal structures.
• ATP-actin monomers are flatter than ADP-actin monomers.
• The pointed end of actin filaments has a distinct, flatter conformation requiring monomer isomerization, slowing polymerization.
• The barbed end adopts a conformation similar to ATP-actin, promoting polymerization.

Conclusions:

• Nucleotide-dependent conformational changes in actin monomers directly influence polymerization kinetics.
• The distinct structures of filament ends create thermodynamic penalties and enhancements that govern polymerization speed.
• Simulation results align with experimental observations of actin polymerization thermodynamics.