title: EGCG in Green Tea Induces Aggregation of HMGB1 Protein through Large Conformational Changes with Polarized Charge Redistribution.
abstract: As a major effective component in green tea, (-)-epigallocatechin-3-gallate (EGCG)'s potential benefits to human health have been widely investigated. Recent experimental evidences indicate that EGCG can induce the aggregation of HMGB1 protein, a late mediator of inflammation, which subsequently stimulates the autophagic degradation and thus provides protection from lethal endotoxemia and sepsis. In this study, we use molecular dynamics (MD) simulations to explore the underlying molecular mechanism of this aggregation of HMGB1 facilitated by EGCG. Our simulation results reveal that EGCG firmly binds to HMGB1 near Cys106, which supports previous preliminary experimental evidence. A large HMGB1 conformational change is observed, where Box A and Box B, two homogenous domains of HMGB1, are repositioned and packed together by EGCG. This new HMGB1 conformation has large molecular polarity and distinctive electrostatic potential surface. We suggest that the highly polarized charge distribution leads to the aggregation of HMGB1, which differs from the previous hypothesis that two HMGB1 monomers are linked by the dimer of EGCG. Possible aggregating modes have also been investigated with potential of mean force (PMF) calculations. Finally, we conclude that the conformation induced by EGCG is more aggregation-prone with higher binding free energies as compared to those without EGCG.
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.|Department of Physiology and Biophysics, Virginia Commonwealth University, School of Medicine, Richmond, Virginia, VA, USA.
authors.forename: Xuan-Yu
authors.initials: XY
authors.lastname: Meng
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
authors.forename: Baoyu
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
authors.forename: Shengtang
authors.initials: S
authors.lastname: Liu
authors.affiliation: IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.
authors.forename: Hongsuk
authors.initials: H
authors.lastname: Kang
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China.|IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598, USA.|Department of Chemistry, Columbia University, New York, NY 10027, USA.
authors.forename: Ruhong
authors.initials: R
authors.lastname: Zhou
mesh_terms: D001665:Binding Sites; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D024243:HMGB1 Protein / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008968:Molecular Conformation / Q000187:drug effects*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D000072417:Protein Domains / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D055672:Static Electricity; D013662:Tea / Q000737:chemistry*
chemical_list: D024243:HMGB1 Protein; D066329:Protein Aggregates; D013662:Tea; D002392:Catechin; C045651:epigallocatechin gallate; D003545:Cysteine