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Evangelos N. Moudrianakis


130A Levi
Department of Biology
Johns Hopkins University
3400 N. Charles Street
Baltimore, MD 21218-2685
Office 410 516-7305
Lab 410 516-7303
Departmental fax 410 516-5213


University of Athens, Greece


Johns Hopkins University


Johns Hopkins University

Research Interests

Assembly and Dynamics of Nucleoproteins and Chromosomes Bioenergetics


Histones Histone octamer
Histone fold Nucleosome
Archaea Protein thermostability


The research activities of this laboratory are focused on the elucidation of the basic rules governing macromolecular assembly and the acquisition of new, "system properties" by these assemblies, i.e., towards an understanding of the rules of linkage between form and function. Diverse experimental systems are utilized in these studies.

Chromosome - Chromatin: The assembly, architecture and the control of transcription of the eukaryotic genetic apparatus are analyzed by cytological, biochemical and biophysical techniques ranging from in vitro cell culture and light and electron microscopy, through analytical ultracentrifugation and gel permeation chromatography, to x-ray crystallography and microcalorimetry. We have established that the histone "core" of the nucleosome is organized as a tripartite protein entity by the assembly of two dimers of H2A-H2B, one on each side of a centrally located H3-H4 tetramer. The contact interfaces of this assembly are considered as regulatory domains in the functional transitions of chromatin and are being probed by chemical, enzymatic and biophysical probes. We determined the crystal structure of the histone octamer to ca. 3Å resolution and the arrangement of its subunits have revealed novel modes for polypeptide assembly (i.e., histone fold, handshake motif) and protein-DNA recognition and binding (i.e., paired element motifs PEMs). The path of the double helix over the histone octamer has been determined and found to be guided by the 12 repetitive PEMs. Using these geometric constraints, a high resolution model for the nucleosome has been obtained and optimized through molecular dynamics simulations in collaboration with Drs. C. S. Tung and A. E. Garcia of Los Alamos. These simulations revealed that the nucleosome fluctuations are dominated by motions in the DNA backbone. The nucleosome is surrounded by a positive ion cloud with an average local density exceeding by a factor of 5-10 the bulk phase ion concentration. We also see high water density at the protein-DNA boundaries, at the DNA grooves and especially between the two apposing gyres of the nucleosomal DNA.

The energetics of the assembly of the nucleosomal components are analyzed microcalorimetrically through collaboration with Dr. E. Freire of the Biocalorimetry Center of this department. The patterns and specificity of protein-DNA interactions are analyzed by chemical, topological and structural methods. Nucleosome reconstitution experiments utilizing core histone subunits (regular and acetylated), transcription factors and specific sequences of circular DNA are in progress.

Bioenergetics: The mechanism of protein thermostability and enzyme thermoactivity in Archaea are studied. Particular emphasis is focused on the role of osmolytes in protein stabilization.

Zipped histone octamer coordinate file (.zip; 94 KB)
Zipped nucleosome coordinate file (.zip; 198 KB)
Zipped octamer and nucleosome coordinate files (.zip; 292 KB)

Representative Publications

Dohm, J.A., Hsu, M.H., Hwu, J.R., Huang, R.C., Moudrianakis, E.N., Lattman, E.E., Gittis, A.G. 2005. Influence of ions, hydration, and the transcriptional inhibitor P4N on the conformations of the Sp1 binding site. J Mol Biol. 349(4):731-44. Epub 2005 Apr 15.

Angelov, D., Lenouvel, F., Hans, F., Muller, C.W., Bouvet, P., Bednar, J., Moudrianakis, E.N., Cadet, J., Dimitrov, S. 2004. The histone octamer is invisible when NF-kappaB binds to the nucleosome. J Biol Chem. 279(41):42374-82. Epub 2004 Jul 21.

Karantza, V., Freire, E., Moudrianakis, E.N. 2001. Thermodynamic studies of the core histones: stability of the octamer subunits is not altered by removal of their terminal domains. Biochemistry. 40(43):13114-23.

Bal, W., Karantza, V., Moudrianakis, E.N., Kasprzak, K.S. 1999. Interaction of Nickel(II) with histones: in vitro binding of nickel(II) to the core histone tetramer. Arch Biochem Biophys. 364(2):161-6.

Akhmanova, A., Miedema, K., Wang, Y., van Bruggen, M., Berden, J.H., Moudrianakis, E.N., Hennig, W. 1997. The localization of histone H3.3 in germ line chromatin of Drosophila males as established with a histone H3.3-specific antiserum. Chromosoma. 106(6):335-47.

Santisteban, M.S., Arents, G., Moudrianakis, E.N., Smith, M.M. 1997. Histone octamer function in vivo: mutations in the dimer-tetramer interfaces disrupt both gene activation and repression. EMBO J. 16(9):2493-506.