Titr-DMD-A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework
David J Reilley1, Jian Wang2, Nikolay V Dokholyan2,3
1Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095-1569, United States.
Journal of Chemical Theory and Computation
|June 24, 2021
Summary
Titr-DMD offers an affordable computational method to study how pH affects protein dynamics and stability. This approach combines coarse-grained simulations with pKa prediction for efficient, atomic-scale analysis.
Area of Science:
- Computational Biochemistry
- Structural Biology
- Protein Dynamics
Background:
- Enzyme stability and activity are pH-dependent, a dynamic property challenging to study experimentally.
- Current computational methods like constant pH molecular dynamics (CpHMD) face limitations in affordable long-timescale sampling and accurate pKa prediction.
Purpose of the Study:
- To introduce Titr-DMD, an economical CpHMD method for studying pH-coupled protein dynamics.
- To overcome the challenges of computational cost and sampling limitations in existing methods.
Main Methods:
- Titr-DMD integrates the quasi-all-atom coarse-grained discrete molecular dynamics (DMD) for conformational sampling.
- Propka is utilized for accurate pKa prediction within the Titr-DMD framework.
- The method enables rapid, atomic-scale simulations on limited computational resources.
Main Results:
- The method was benchmarked on proteins with known experimental pKa values.
- Titr-DMD successfully analyzed a pH-triggered conformational change in a staphylococcal nuclease mutant.
- Demonstrated effectiveness and cost-efficiency in studying pH-coupled protein dynamics.
Conclusions:
- Titr-DMD provides an effective and inexpensive computational tool for investigating pH-dependent protein behavior.
- The method facilitates the study of dynamic, structural properties influenced by pH on limited computational budgets.
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