Conformational sampling using high-temperature molecular dynamics.

Area of Science:

• Computational chemistry
• Structural biology
• Biophysics

Background:

• Understanding antibody-antigen interactions is crucial for drug design.
• Conformational flexibility of antibodies influences antigen binding.
• Molecular dynamics (MD) simulations are used to study protein dynamics.

Purpose of the Study:

• To evaluate high-temperature molecular dynamics (HTMD) as a method for conformational searching.
• To explore the antigen combining site of McPC 603, a phosphorylcholine-binding immunoglobulin.
• To compare HTMD with direct conformational search methods.

Main Methods:

• Simulations of McPC 603 antigen site at 500 K, 800 K, and 1500 K.
• Assessing conformational space coverage using theoretical models and geometric measures.
• Minimizing simulated structures to evaluate their energy.
• Comparing HTMD results with a direct conformational search method.

Main Results:

• Shorter hypervariable loops explored significant conformational space at high temperatures.
• Simulations at 500 K and 800 K yielded structures with energies 200 kcal/mole lower than the crystal structure.
• 1500 K simulations resulted in higher energy structures and numerous cis-trans peptide isomerizations.
• High-temperature MD and direct search methods explored largely distinct conformational spaces.

Conclusions:

• High-temperature molecular dynamics can be a valuable tool for exploring protein conformational landscapes.
• Temperatures around 500-800 K appear more suitable for conformational sampling than 1500 K.
• Simulation duration and temperature are critical parameters for effective conformational searching using MD.