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Analysis of the structure and dynamics of human serum albumin

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Abstract

Human serum albumin (HSA) is a biologically relevant protein that binds a variety of drugs and other small molecules. No less than 50 structures are deposited in the RCSB Protein Data Bank (PDB). Based on these structures, we first performed a clustering analysis. Despite the diversity of ligands, only two well defined conformations are detected, with a deviation of 0.46 nm between the average structures of the two clusters, while deviations within each cluster are smaller than 0.08 nm. Those two conformations are representative of the apoprotein and the HSA-myristate complex already identified in previous literature. Considering the structures within each cluster as a representative sample of the dynamical states of the corresponding conformation, we scrutinize the structural and dynamical differences between both conformations. Analysis of the fluctuations within each cluster set reveals that domain II is the most rigid one and better matches both structures. Then, taking this domain as reference, we show that the structural difference between both conformations can be expressed in terms of twist and hinge motions of domains I and III, respectively. We also characterize the dynamical difference between conformations by computing correlations and principal components for each set of dynamical states. The two conformations display different collective motions. The results are compared with those obtained from the trajectories of short molecular dynamics simulations, giving consistent outcomes. Let us remark that, beyond the relevance of the results for the structural and dynamical characterization of HAS conformations, the present methodology could be extended to other proteins in the PDB archive.

Two conformations of the human serum albumin were found in a cluster analysis of data available in the Protein Data Bank. X1 and X2 are structures representatives of each cluster. Both X1 and X2 represent the apo protein and the HSA-myristate conformations respectively. Two predominant motions of X2 with respect to X1 are observed, the first one shows a separation hinge motion (15°) of domain III, the second a twist motion of domain I (24°). A discussion of the residues involved in the conformational change as well a comparison between the experimental and theoretical (obtained from molecular dynamics) principal component analysis is performed.

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Acknowledgments

We acknowledge CAPES/Brazil (under the project “Integrated Action on Chemical Nanotechnology” No. 02559/09-9), Faperj (Foundation for Research Support, State of Rio de Janeiro) and CNPq (National Council for Scientific and Technological Development) for partial financial support. We also acknowledge the developers of the free software Gromacs [24].

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Authors and Affiliations

  1. Physics Department, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro, Brazil

    T. R. Cuya Guizado

  2. Chemistry Department, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro, Brazil

    T. R. Cuya Guizado

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Correspondence to T. R. Cuya Guizado.

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This paper belongs to Topical Collection Brazilian Symposium of Theoretical Chemistry (SBQT2013)

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Guizado, T.R.C. Analysis of the structure and dynamics of human serum albumin. J Mol Model 20, 2450 (2014). https://doi.org/10.1007/s00894-014-2450-y

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