A Two-Ended Data-Driven Accelerated Sampling Method for Exploring the Transition Pathways between Two Known States of
Yigao Yuan1, Qiang Zhu1,2, Ruiheng Song1
1Kuang Yaming Honors School, Nanjing University, 210023 Nanjing, China.
Journal of Chemical Theory and Computation
|April 23, 2020
Summary
We developed a new method, teDA2, for efficiently simulating protein conformational changes. This approach accurately captures protein dynamics and flexibility, revealing multiple transition pathways for adenylate kinase.
Area of Science:
- Biophysics
- Computational Biology
- Structural Biology
Background:
- Protein conformational transitions are crucial for biological function but challenging to study experimentally due to resolution limitations.
- Molecular dynamics (MD) simulations face challenges in adequately sampling protein configuration space.
Purpose of the Study:
- To introduce a novel, robust, data-driven method for enhanced conformational sampling of proteins.
- To apply this method to explore the functional conformational transitions of adenylate kinase (ADK).
Main Methods:
- Proposed the two-ended data-driven accelerated (teDA2) conformational sampling method.
- teDA2 utilizes an adaptively updated feature space without bias potentials.
- Applied teDA2 to study adenylate kinase, a model protein with known open and closed states.
Main Results:
- Achieved single conformational transition events of ADK within tens of nanoseconds.
- Reproduced literature-reported mechanisms and pathways for ADK domain motion by analyzing hundreds of transitions.
- Identified metastable states resembling crystal structures, confirming ADK's multiroute conformational plasticity.
- Validated findings using Markov state modeling with independent MD simulations.
Conclusions:
- teDA2 is a reliable and efficient enhanced sampling protocol for studying protein dynamics.
- Protein conformational plasticity arises from inherent flexibility, enabling multiroute transitions.
- The method is broadly applicable to various biomolecular machines and their functional states.
