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An Efficient Strategy for the Estimation of Rare Event Transition Times in Biomolecular Systems
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH).
Structural Biology and NMR Laboratory, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen.ORCID iD: 0000-0001-9156-0377
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-8198-9284
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Studies of kinetics in biological systems are important for understanding functions of biomolecules and can provide valuable information for drug discovery. However, how to obtain the kinetics closely related to a rare event occurring in a biomolecular system from conventional unbiased molecular dynamics (MD) simulations remains a big challenge. Recently, an enhanced sampling method, namely infrequent metadynamics (InMetaD), has been developed and has the capability to recover the unbiased transition time from metadynamic runs. However, in this method a bias potential is deposited to the system at a low frequency, which often makes most of the computational time spend in waiting for the simulated system escaping from the initial state. Here we propose a strategy to achieve the same goal as InMetaD with increased efficiency. In this strategy, we first accelerate the occurring of a rare event using metadynamics simulations with a high bias deposition frequency, and subsequently restart the simulations at a time point before the rare event occurs, but with a low bias deposition frequency. Through combining these simulation data, the unbiased transition time can be recovered in the same way as in InMetaD. We applied this strategy to the studies of three systems including the conformational change of a small peptide, unfolding of a protein, and unbinding of an intrinsically disordered protein from its target. We show that our strategy can improve the efficiency in estimating the unbiased transition times in a very convenient way.

Keywords [en]
enhanced sampling, infrequent metadynamics, kinetics, rare-event
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:kth:diva-251310OAI: oai:DiVA.org:kth-251310DiVA, id: diva2:1314965
Note

QC 20190619

Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-06-19Bibliographically approved
In thesis
1. Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
Open this publication in new window or tab >>Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on studies of protein-ligand systems using enhanced sampling methods. In chapter I, I give a brief introduction to the time-scale problem and some enhanced sampling methods. In chapter II, the basics of MD simulation are reviewed. In chapter III, the theoretical backgrounds of umbrella sampling, bias-exchange metadynamics and infrequent metadynamics are presented. In chapter IV, the 5 papers included in this thesis are summarized. In paper 1, we studied the relationship between the antibacterial activities of antimicrobial peptides and their aggregation propensities. We found that an increasing aggregation propensity increases the free energy cost of peptide embedding into the bacterial membrane and decreases antibacterial activity. In paper 2, we employed the umbrella sampling approach to obtain the free energy landscape of Pittsburgh compound-B penetrating into the core binding sites of amyloid βfibrils. Our study suggested that, for the design of probes binding to fibril like proteins, other than the binding affinity, the dynamics of probes in the fibrils should also be considered. In paper 3, we studied the coupled folding and binding process of the intrinsically disordered protein p53 to MDM2 with bias-exchange metadynamics and infrequent metadynamics. We reconstructed the free energy landscape and built a kinetic network for this process. In paper 4, we studied the binding modes of ASEM with a chimera structure of α7 nicotinic acetylcholine receptor with well-tempered metadynamics. We found that an important residue, Trp53, can significantly affect the stabilities of the binding modes. In paper 5, we proposed an efficient method to estimate the transition times of rare events in biomolecular systems. In chapter V, I present a conclusion of this thesis and propose an outlook related to the selection of collective variables for enhanced sampling methods.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019. p. 58
Series
TRITA-CBH-FOU ; 34
Keywords
molecular dynamics, enhanced sampling, protein-ligand interactions, umbrella sampling, metadynamics
National Category
Natural Sciences
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-251025 (URN)
Public defence
2019-06-05, FP41, Roslagstullsbacken 33, Byggnad 1, floor 4, AlbaNova, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 2019-05-10

Available from: 2019-05-10 Created: 2019-05-08 Last updated: 2019-05-10Bibliographically approved

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