Domain motions

Hayward, S., Kitao, A., Berendsen, H.J.C. Model-free methods to analyze domain motions in proteins from simulation A comparison of normal mode analysis and molecular dynamics simulation of lysozyme. Proteins 27 (1997) 425-437. 

Protein dynamics occurs on very different time scales ([McCammon and Harvey 1987, Jardetzky 1996]). Here, we are most interested in long time scale motions such as relative motion between secondary structure elements, and inter-domain motion. 

We have previously calculated conformational free energy differences for a well-suited model system, the catalytic subunit of cAMP-dependent protein kinase (cAPK), which is the best characterized member of the protein kinase family. It has been crystallized in three different conformations and our main focus was on how ligand binding shifts the equilibrium among these ([Helms and McCammon 1997]). As an example using state-of-the-art computational techniques, we summarize the main conclusions of this study and discuss a variety of methods that may be used to extend this study into the dynamic regime of protein domain motion. 

Domain motion Hmge-bendmg motion Microseconds (ps) to milli-... 

Hinsen, K., Analysis of domain motions by approximate normal mode calculations, Proteins Struct. Funct. Genet. 1998, 33, 417-429... 

Structural characterization of NRPSs has yielded significant insight into the enzymology of these complex biosynthetic machines and has provided a framework for engineering these systems toward novel function. As summarized in this section, X-ray crystal and NMR structures have been determined for both individual NRPS domains and multidomain constructs. Overall, these studies support a monomeric structure for NRPS assembly line units where significant domain motion is necessary to allow participation of the various active sites in the chemistry leading to peptide products. 

The MARTINI model effectively replaces three to four heavy atoms with a bead, parameterized to reproduce condensed-phase thermodynamic data of small molecules [23]. The MARTINI model has been used to investigate many biological processes, such as lung surfactant collapse [24], nanoparticle permeation in bilayers [25], large domain motion of integral membrane proteins [26], vesicle fusion [27,28], and lateral domain formation in membranes [29]. 

Arnold GE, Omstein RL. Molecular dynamics study of time-correlated protein domain motions and molecular flexibility cytochrome P450BM-3. Biophys J 1997 73 1147-1159. 

K. Hinsen, Proteins Struct., Genet., Fund., 33,417 (1998). Analysis of Domain Motions by... 

Guddat, L. W., Bardwell,J. C., andMartin.J. L. (1998). Crystal structures of reduced and oxidized DsbA investigation of domain motion and thiolate stabilization. Structure, 6, 757-767. 

The internal motion of T4 lysozyme in the crystal was interpreted as an inter-domain motion corresponding to opening and closing of the active site cleft (Weaver et al., 1989). Hinge-bending and substrate-induced conformational transition in T4 lysozyme in solution were confirmed in a study by site-directed labelling (Mchaourban et al., 1997). 

Neutron spectroscopy is becoming a principal tool for the study of protein dynamics (Cusack, 1986, 1989 Middendorf, 1984 Middendorf et al., 1984). Current instruments cover motions with characteristic times from 10 to 10 sec. This range embraces essentially all protein modes excited at room temperature (the soft modes), including motions of the solvent shell and also low-frequency large-scale domain motions, like the hinge-bending motion of the lysozyme domains that form the... 

In unimolecular ET, the rate can be controlled by large-scale cofactor motion, such as the quinone motion in the photosynthetic reaction centers, the Rieske subunit motion in the cytochrome bc complex (47), or the cytochrome fcs-domain in sulfite oxidase. Theoretical models for conformationally controlled ET reactions have been suggested by Hoffman and Rat-ner (48) and Bnmschwig and Sutin (49). Large-scale protein or domain motions are themselves linked to the movement of water molecules. 

Interesting applications of anisotropy decays for proteins often develop not from tumbling of the protein as a whole, but from other reorientational degrees of freedom. These motions may include protein domain motions or segmental motions in proteins and peptides. The anisotropy decay in this case is non-single-exponential (see Fig. 4c) and takes the form ... 

Another aspect of enzyme function, which can be readily studied by methods based on empirical energy functions, are large scale atomic displacements, such as domain motions and conformational transitions of loops. The energy as a function of the relative positions of domains or loops can be obtained through several techniques... 

Lysozyme is a key system in the development of our understanding of the structure and function of proteins. It was the first enzyme whose x-ray structure was determined at high resolution (Blake et al. 1965), one of the earliest enzymes for which a detailed reaction mechanism was proposed and one of the test systems for molecular dynamics simulations. In this section, we review some of the simulation studies of lysozyme with emphasis on the reaction mechanism and on the large scale domain motion involved in the mechanism. 

Most of the information on interdomain motions come from high-resolution crystal structures several reviews are available (Janin and Wodak 1983 Bennett andHuber 1984 Gerstein et al. 1994). Calculations ofhinge bending modes and domain motions in proteins other than lysozyme have been made. They include antibody molecules where the interdomain motions occur on a nanosecond time scale (McCammon and Karplus 1977 Oi et al. 1984), 1-arabinose-binding protein (Mao et al. 1982), liver alcohol dehydrogenase (Colona-Cesari et al. 1986) and the mouse... 

Bennett, W. S. and Huber, R. (1984) Structural and Functional Aspects of Domain Motions in Proteins, Crit. Rev. Biochem. 15, 291-384. 

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