An Accelerated Molecular Dynamics Study for Investigating Protein Pathways Using the Bond-boost Hyperdynamics Method

Overview

Journal Protein Sci

Specialty Biochemistry

Date 2025 Feb 25

PMID 39998983

Authors

Soon Woo Park

Moon-Ki Choi

Byung Ho Lee

Sangjae Seo

Woo Kyun Kim

Moon Ki Kim

Affiliations

Soon will be listed here.

Abstract

Molecular dynamics (MD) simulation is an important tool for understanding protein dynamics and the thermodynamic properties of proteins. However, due to the high computational cost of MD simulations, it is still challenging to explore a wide conformational space. To solve this problem, a variety of accelerated MD (aMD) schemes have been proposed over the past few decades. The bond-boost method (BBM) is one of such aMD schemes, which expedites escape events from energy basins by adding a bias potential based on changes in bond length. In this paper, we present a new methodology based on the BBM for accelerating the conformational transition of proteins. In our modified BBM, the bias potential is constructed using the dihedral angle and hydrogen bond, which are more suitable variables to monitor the conformational change in proteins. Additionally, we have developed an efficient algorithm compatible with the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS) package. The method is validated with the conformational change of ribose binding protein and adenylate kinase by comparing the conventional and accelerated MD simulation results. Based on the aMD results, the characteristics of the proteins are investigated by monitoring the conformational transition pathways. Moreover, the free energy landscape calculated using umbrella sampling confirms all the states identified by the aMD simulation are the free energy minima, and the system makes transitions following the path indicated by the free energy landscape. Our efficient approach is expected to play a key role in investigating transition pathways in a wide range of protein simulations.

References

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

Sun J, He L, Lo Y, Xu T, Bi H, Sun L . Liquid-like pseudoelasticity of sub-10-nm crystalline silver particles. Nat Mater. 2014; 13(11):1007-12. DOI: 10.1038/nmat4105. View

Farrell D, Speranskiy K, Thorpe M . Generating stereochemically acceptable protein pathways. Proteins. 2010; 78(14):2908-21. DOI: 10.1002/prot.22810. View

Beckstein O, Denning E, Perilla J, Woolf T . Zipping and unzipping of adenylate kinase: atomistic insights into the ensemble of open<-->closed transitions. J Mol Biol. 2009; 394(1):160-76. PMC: 2803350. DOI: 10.1016/j.jmb.2009.09.009. View

Bahar I, Lezon T, Bakan A, Shrivastava I . Normal mode analysis of biomolecular structures: functional mechanisms of membrane proteins. Chem Rev. 2009; 110(3):1463-97. PMC: 2836427. DOI: 10.1021/cr900095e. View

Muller C, Schlauderer G, Reinstein J, Schulz G . Adenylate kinase motions during catalysis: an energetic counterweight balancing substrate binding. Structure. 1996; 4(2):147-56. DOI: 10.1016/s0969-2126(96)00018-4. View

Henin J, Chipot C . Overcoming free energy barriers using unconstrained molecular dynamics simulations. J Chem Phys. 2004; 121(7):2904-14. DOI: 10.1063/1.1773132. View

Kim W, Falk M . A practical perspective on the implementation of hyperdynamics for accelerated simulation. J Chem Phys. 2015; 140(4):044107. DOI: 10.1063/1.4862269. View

Ye C, Ding C, Ma R, Wang J, Zhang Z . Electrostatic interactions determine entrance/release order of substrates in the catalytic cycle of adenylate kinase. Proteins. 2019; 87(4):337-347. DOI: 10.1002/prot.25655. View

10.

Kubitzki M, de Groot B . The atomistic mechanism of conformational transition in adenylate kinase: a TEE-REX molecular dynamics study. Structure. 2008; 16(8):1175-82. DOI: 10.1016/j.str.2008.04.013. View

11.

Sali A, Blundell T . Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol. 1993; 234(3):779-815. DOI: 10.1006/jmbi.1993.1626. View

12.

Lou H, Cukier R . Molecular dynamics of apo-adenylate kinase: a principal component analysis. J Phys Chem B. 2006; 110(25):12796-808. DOI: 10.1021/jp061976m. View

13.

Dokainish H, Sugita Y . Exploring Large Domain Motions in Proteins Using Atomistic Molecular Dynamics with Enhanced Conformational Sampling. Int J Mol Sci. 2021; 22(1). PMC: 7796230. DOI: 10.3390/ijms22010270. View

14.

Bjorkman A, Binnie R, Zhang H, Cole L, Hermodson M, Mowbray S . Probing protein-protein interactions. The ribose-binding protein in bacterial transport and chemotaxis. J Biol Chem. 1994; 269(48):30206-11. View

15.

Notredame C, Higgins D, Heringa J . T-Coffee: A novel method for fast and accurate multiple sequence alignment. J Mol Biol. 2000; 302(1):205-17. DOI: 10.1006/jmbi.2000.4042. View

16.

Maier J, Martinez C, Kasavajhala K, Wickstrom L, Hauser K, Simmerling C . ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J Chem Theory Comput. 2015; 11(8):3696-713. PMC: 4821407. DOI: 10.1021/acs.jctc.5b00255. View

17.

Bhatt D, Zuckerman D . Heterogeneous path ensembles for conformational transitions in semi-atomistic models of adenylate kinase. J Chem Theory Comput. 2011; 6(11):3527-3539. PMC: 3108504. DOI: 10.1021/ct100406t. View

18.

Hoover . Canonical dynamics: Equilibrium phase-space distributions. Phys Rev A Gen Phys. 1985; 31(3):1695-1697. DOI: 10.1103/physreva.31.1695. View

19.

Allner O, Nilsson L, Villa A . Magnesium Ion-Water Coordination and Exchange in Biomolecular Simulations. J Chem Theory Comput. 2015; 8(4):1493-502. DOI: 10.1021/ct3000734. View

20.

Bellinzoni M, Haouz A, Grana M, Munier-Lehmann H, Shepard W, Alzari P . The crystal structure of Mycobacterium tuberculosis adenylate kinase in complex with two molecules of ADP and Mg2+ supports an associative mechanism for phosphoryl transfer. Protein Sci. 2006; 15(6):1489-93. PMC: 2242552. DOI: 10.1110/ps.062163406. View