Serpin latency transition at atomic resolution.

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biophysics

Background:

• Serpins undergo significant conformational changes for protease inhibition, transitioning from active to inactive states.
• Latency transitions in serpins can occur without proteases but are too slow for conventional molecular dynamics simulations.

Purpose of the Study:

• To simulate the complete active-to-latent conformational transition of serpins at an all-atom level.
• To elucidate the mechanism of latency transitions and explain experimental data for plasminogen activator inhibitor-1 (PAI-1).
• To investigate factors influencing conformational lability in different serpin families.

Main Methods:

• Employed a variational path sampling algorithm for molecular dynamics simulations.
• Utilized a physically realistic force field on a standard computing cluster.
• Simulated the entire active-to-latent transition for serpins, including PAI-1 variants.

Main Results:

• Successfully simulated the complete serpin active-to-latent transition, explaining PAI-1 latency.
• Predicted a long-lived prelatent intermediate state, consistent with prior hypotheses.
• Accurately predicted the kinetic effects of PAI-1 mutations and identified potential ligand targets.

Conclusions:

• The simulations provide a unified mechanism for serpin latency transitions.
• The study highlights differences in conformational lability between serpin families, exemplified by PAI-1 and alpha-1-antitrypsin.
• Findings offer a pathway for designing ligands to modulate serpin latency kinetics.