Complete Protein-protein Association Kinetics in Atomic Detail Revealed by Molecular Dynamics Simulations and Markov Modelling

Overview

Journal Nat Chem

Specialty Chemistry

Date 2017 Sep 23

PMID 28937668

Citations 125

Authors

Nuria Plattner

Stefan Doerr

Gianni De Fabritiis

Frank Noe

Affiliations

Soon will be listed here.

Abstract

Protein-protein association is fundamental to many life processes. However, a microscopic model describing the structures and kinetics during association and dissociation is lacking on account of the long lifetimes of associated states, which have prevented efficient sampling by direct molecular dynamics (MD) simulations. Here we demonstrate protein-protein association and dissociation in atomistic resolution for the ribonuclease barnase and its inhibitor barstar by combining adaptive high-throughput MD simulations and hidden Markov modelling. The model reveals experimentally consistent intermediate structures, energetics and kinetics on timescales from microseconds to hours. A variety of flexibly attached intermediates and misbound states funnel down to a transition state and a native basin consisting of the loosely bound near-native state and the tightly bound crystallographic state. These results offer a deeper level of insight into macromolecular recognition and our approach opens the door for understanding and manipulating a wide range of macromolecular association processes.

Citing Articles

Ionic liquids as stabilisers of therapeutic protein formulations: a review of insulin and monoclonal antibodies.

Tien S, Kayser V Biophys Rev. 2025; 17(1):89-101.

PMID: 40060006 PMC: 11885717. DOI: 10.1007/s12551-024-01261-y.

AMARO: All Heavy-Atom Transferable Neural Network Potentials of Protein Thermodynamics.

Mirarchi A, Pelaez R, Simeon G, De Fabritiis G J Chem Theory Comput. 2024; 20(22):9871-9878.

PMID: 39514694 PMC: 11603603. DOI: 10.1021/acs.jctc.4c01239.

Computational screening of the effects of mutations on protein-protein off-rates and dissociation mechanisms by τRAMD.

DArrigo G, Kokh D, Nunes-Alves A, Wade R Commun Biol. 2024; 7(1):1159.

PMID: 39289580 PMC: 11408511. DOI: 10.1038/s42003-024-06880-5.

Structure prediction of alternative protein conformations.

Bryant P, Noe F Nat Commun. 2024; 15(1):7328.

PMID: 39187507 PMC: 11347660. DOI: 10.1038/s41467-024-51507-2.

Protein Retrieval via Integrative Molecular Ensembles (PRIME) through Extended Similarity Indices.

Chen L, Mondal A, Perez A, Alain Miranda-Quintana R J Chem Theory Comput. 2024; 20(14):6303-6315.

PMID: 38978294 PMC: 11807272. DOI: 10.1021/acs.jctc.4c00362.

References

Trendelkamp-Schroer B, Wu H, Paul F, Noe F . Estimation and uncertainty of reversible Markov models. J Chem Phys. 2015; 143(17):174101. DOI: 10.1063/1.4934536. View

Plattner N, Noe F . Protein conformational plasticity and complex ligand-binding kinetics explored by atomistic simulations and Markov models. Nat Commun. 2015; 6:7653. PMC: 4506540. DOI: 10.1038/ncomms8653. View

Schreiber G, Haran G, Zhou H . Fundamental aspects of protein-protein association kinetics. Chem Rev. 2009; 109(3):839-60. PMC: 2880639. DOI: 10.1021/cr800373w. View

Best R, Zhu X, Shim J, Lopes P, Mittal J, Feig M . Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles. J Chem Theory Comput. 2013; 8(9):3257-3273. PMC: 3549273. DOI: 10.1021/ct300400x. View

Doerr S, Harvey M, Noe F, De Fabritiis G . HTMD: High-Throughput Molecular Dynamics for Molecular Discovery. J Chem Theory Comput. 2016; 12(4):1845-52. DOI: 10.1021/acs.jctc.6b00049. View

Frisch C, Fersht A, Schreiber G . Experimental assignment of the structure of the transition state for the association of barnase and barstar. J Mol Biol. 2001; 308(1):69-77. DOI: 10.1006/jmbi.2001.4577. View

Schluttig J, Alamanova D, Helms V, Schwarz U . Dynamics of protein-protein encounter: a Langevin equation approach with reaction patches. J Chem Phys. 2008; 129(15):155106. DOI: 10.1063/1.2996082. View

Bowman G, Ensign D, Pande V . Enhanced modeling via network theory: Adaptive sampling of Markov state models. J Chem Theory Comput. 2013; 6(3):787-94. PMC: 3637129. DOI: 10.1021/ct900620b. View

Chung H, McHale K, Louis J, Eaton W . Single-molecule fluorescence experiments determine protein folding transition path times. Science. 2012; 335(6071):981-4. PMC: 3878298. DOI: 10.1126/science.1215768. View

10.

Tiwary P, Parrinello M . From metadynamics to dynamics. Phys Rev Lett. 2014; 111(23):230602. DOI: 10.1103/PhysRevLett.111.230602. View

11.

Lindorff-Larsen K, Piana S, Dror R, Shaw D . How fast-folding proteins fold. Science. 2011; 334(6055):517-20. DOI: 10.1126/science.1208351. View

12.

Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C . Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins. 2006; 65(3):712-25. PMC: 4805110. DOI: 10.1002/prot.21123. View

13.

Preto J, Clementi C . Fast recovery of free energy landscapes via diffusion-map-directed molecular dynamics. Phys Chem Chem Phys. 2014; 16(36):19181-91. DOI: 10.1039/c3cp54520b. View

14.

Hartley R . Directed mutagenesis and barnase-barstar recognition. Biochemistry. 1993; 32(23):5978-84. DOI: 10.1021/bi00074a008. View

15.

Schreiber G, Fersht A . Energetics of protein-protein interactions: analysis of the barnase-barstar interface by single mutations and double mutant cycles. J Mol Biol. 1995; 248(2):478-86. DOI: 10.1016/s0022-2836(95)80064-6. View

16.

Schreiber G, Fersht A . Rapid, electrostatically assisted association of proteins. Nat Struct Biol. 1996; 3(5):427-31. DOI: 10.1038/nsb0596-427. View

17.

Perez-Hernandez G, Paul F, Giorgino T, De Fabritiis G, Noe F . Identification of slow molecular order parameters for Markov model construction. J Chem Phys. 2013; 139(1):015102. DOI: 10.1063/1.4811489. View

18.

Levy Y, Wolynes P, Onuchic J . Protein topology determines binding mechanism. Proc Natl Acad Sci U S A. 2003; 101(2):511-6. PMC: 327178. DOI: 10.1073/pnas.2534828100. View

19.

Noe F, Wu H, Prinz J, Plattner N . Projected and hidden Markov models for calculating kinetics and metastable states of complex molecules. J Chem Phys. 2013; 139(18):184114. DOI: 10.1063/1.4828816. View

20.

Spaar A, Dammer C, Gabdoulline R, Wade R, Helms V . Diffusional encounter of barnase and barstar. Biophys J. 2005; 90(6):1913-24. PMC: 1386772. DOI: 10.1529/biophysj.105.075507. View