Protein folding mechanisms reaction coordinates

Proteins. The questions, What kinds of mechanisms carry a protein into an unique native state and What is the best reaction coordinate to describe the dynamics of protein folding have been among the most intriguing subjects over the past decades in biological physics [35,36]. The process of protein folding may be interpreted as a normal Brownian process of a few collective... 

The general problems on proteins that can be in principle solved via MM simulations are (1) the construction of three-dimensional structure of the macromolecule and prediction of the pathways of protein folding using restricted experimental data (ideally, the primary structure only) (2) the refinement of experimental structure (X-ray diffraction patterns usually do not supply us with information sufficient for precise atom coordinate assignment). The whole problem of the proteins functioning as enzymes cannot be solved via MM only, as chemical reactions are beyond the MM approach, quantum mechanics considerations are indispensable. Nevertheless, the MM approach is useful for the problems of enzyme-substrate complex formation and of molecular recognition, which are crucial for protein functions. 

Before our work [39], only one catalytic mechanism for zinc dependent HDACs has been proposed in the literature, which was originated from the crystallographic study of HDLP [47], a histone-deacetylase-like protein that is widely used as a model for class-I HDACs. In the enzyme active site, the catalytic metal zinc is penta-coordinated by two asp residues, one histidine residues as well as the inhibitor [47], Based on their crystal structures, Finnin et al. [47] postulated a catalytic mechanism for HDACs in which the first reaction step is analogous to the hydroxide mechanism for zinc proteases zinc-bound water is a nucleophile and Zn2+ is five-fold coordinated during the reaction process. However, recent experimental studies by Kapustin et al. suggested that the transition state of HDACs may not be analogous to zinc-proteases [48], which cast some doubts on this mechanism. 

CAD is a 1.5 Mda complex that catalyzes the first three steps in de novo pyrimidine biosynthesis in mammalian cells. The protein consists of six copies of a 243 kDa polypeptide that is organized into 15 domains, subdomains and linkers each with a specific catalytic or regulatory function. Most of these domains have been subcloned and expressed in E. coli where they fold into stable, fully functional proteins. While each domain functions autonomously, interdomain signaling modulates the reactions occurring on different domains to ensure that biosynthesis proceeds in a coordinated fashion. Insights into the signaling mechanism have been provided by the analysis of several hybrid and chimeric molecules constructed by combining domains and subdomains of the mammalian, yeast and E. coli proteins in novel ways. 

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