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Journal article
Minimal Collective Variables for Conformational Transitions in Steered and Temperature-Accelerated MD Simulations: A T4 Lysozyme Case Study
The journal of physical chemistry. B, v 129(21), pp 5176-5188
15 May 2025
PMID: 40375602
Featured in Collection : Research Supported by Drexel Libraries' OA Programs
Abstract
Conformational transitions in proteins can be difficult to observe with equilibrium molecular dynamics and challenging for enhanced sampling methods like Targeted MD when high-resolution structural data are unavailable. Low-resolution data, such as interatomic distances and angles, can serve as collective variables (CVs) to bias steered MD (SMD) simulations, but the optimal choice and number of CVs remain unclear. Here, we identify a minimal set of CVs that drive successful transitions between metastable states in T4 lysozyme. We validate them using temperature-accelerated MD (TAMD) to accelerate conformational changes in the absence of target bias. We found that CVs at both the largest and smallest scales are necessary, including interdomain hinge bending and local side-chain reorientation. A salt bridge between Arg8 and Glu64 stabilizes the closed state and must break for hinge bending, while Phe4 reorients to a hydrophobic pocket to stabilize the open state. Our results highlight the importance of selecting appropriate CVs and optimizing the steering protocol to prevent protein deformation. This work demonstrates that SMD simulations can serve as a predictive tool for understanding protein conformational changes in the absence of high-resolution structural data.
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Details
- Title
- Minimal Collective Variables for Conformational Transitions in Steered and Temperature-Accelerated MD Simulations: A T4 Lysozyme Case Study
- Creators
- Salsabil Abou-Hatab (Corresponding Author) - Drexel UniversityCameron F Abrams - Drexel University
- Publication Details
- The journal of physical chemistry. B, v 129(21), pp 5176-5188
- Publisher
- ACS Publications; WASHINGTON
- Number of pages
- 13
- Grant note
- National Institute of Allergy and Infectious Diseases: R01-AI178833 National Institutes of Health (NIH)
This research was funded by the National Institutes of Health (NIH) under grant R01-AI178833.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Chemical and Biological Engineering
- Web of Science ID
- WOS:001490127400001
- Scopus ID
- 2-s2.0-105005196313
- Other Identifier
- 991022053728604721
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- Web of Science research areas
- Chemistry, Physical