A computational method to simulate global conformational changes of proteins induced by cosolvent

Area of Science:

• Computational chemistry
• Biophysics
• Molecular dynamics

Background:

• Protein conformational changes are crucial for biological function.
• Simulating these changes, especially in solution, presents significant computational challenges.
• Understanding denaturation mechanisms, like urea-induced unfolding, requires accurate and efficient methods.

Purpose of the Study:

• To develop and validate a novel computational method for investigating protein global conformational changes.
• To assess the efficiency and accuracy of the proposed method in simulating solution-induced denaturation.
• To elucidate the mechanism of urea-induced denaturation of ubiquitin.

Main Methods:

• Combining Linear Response Path Following (LRPF) with 3D Reference Interaction Site Model (3D-RISM) theory into a hybrid LRPF/3D-RISM method.
• Applying the LRPF/3D-RISM method to simulate the urea-induced denaturation of ubiquitin.
• Comparing simulation results with standard Molecular Dynamics (MD) simulations.

Main Results:

• The LRPF/3D-RISM method successfully simulated the early stages of ubiquitin denaturation by urea within 300 ns.
• Standard MD simulations of 1 μs showed no significant structural changes, highlighting the efficiency of LRPF/3D-RISM.
• The simulated denaturation mechanism aligns with previously reported findings for urea denaturation of ubiquitin.

Conclusions:

• The LRPF/3D-RISM method offers a computationally efficient and accurate approach for studying protein conformational dynamics in solution.
• This method is particularly effective for simulating processes like cosolvent-induced denaturation.
• The study validates the LRPF/3D-RISM approach for investigating complex protein behavior and provides insights into ubiquitin denaturation.