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. 2009 Jun 17;96(12):4993-5002.
doi: 10.1016/j.bpj.2009.03.051.

Coarse-grained description of protein internal dynamics: an optimal strategy for decomposing proteins in rigid subunits

R Potestio  1 , F Pontiggia, C Micheletti
Affiliations

Coarse-grained description of protein internal dynamics: an optimal strategy for decomposing proteins in rigid subunits

R Potestio et al. Biophys J. .

Abstract

The possibility of accurately describing the internal dynamics of proteins, in terms of movements of a few approximately-rigid subparts, is an appealing biophysical problem with important implications for the analysis and interpretation of data from experiments or numerical simulations. The problem is tackled here by means of a novel variational approach that exploits information about equilibrium fluctuations of interresidues distances, provided, e.g., by atomistic molecular dynamics simulations or coarse-grained models. No contiguity in primary sequence or in space is enforced a priori for amino acids grouped in the same rigid unit. The identification of the rigid protein moduli, or dynamical domains, provides valuable insight into functionally oriented aspects of protein internal dynamics. To illustrate this point, we first discuss the decomposition of adenylate kinase and HIV-1 protease and then extend the investigation to several representatives of the hydrolase enzymatic class. The known catalytic site of these enzymes is found to be preferentially located close to the boundary separating the two primary dynamical subdomains.

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Figures

Figure 1
Figure 1
(a) First essential mode of E. coli adenylate kinase. Subdivisions of the enzyme in Q = 3 and Q = 4 rigid subunits, identified by different colors, are shown in panels b and c. The decomposition was performed taking into account the 10 lowest-energy modes. For clarity, only the rigid-body approximation to the first mode is shown. The fraction of essential dynamical motion (see Eq. 5) captured by the subdivision into Q = 2…10 rigid domains is shown in panel d. Panels e–i show analogous results for HIV-1 protease. The two catalytic residues (Asp25 and Asp124) are highlighted in green in the three-dimensional structure.
Figure 2
Figure 2
Distribution of amino acid distances from the boundary separating the two primary dynamical subdomains. The dashed line indicates the distribution of boundary distances for all 2690 amino acids in the data set of Table 1, while the thick line gives the distribution only for the 34 catalytic amino acids. Both distributions are normalized.
Figure 3
Figure 3
Subdivision into Q = 2 dynamical domains (represented in different colors) of exonuclease III (a), human adenovirus proteinase (b), and endo-1,3-1,4-β-D-glucan 4-glucanohydrolase (c). The decomposition was performed taking into account the 10 lowest-energy modes. For clarity, only the rigid-body approximation to the first mode is shown. Catalytic residues are shown as spheres.
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