Native-state dynamics of the ubiquitin family: implications for function and evolution

Protein dynamics are integral to protein function. In recent years, the use of computer simulation to understand the molecular motions of proteins has become widespread. However, there are few such studies which compare the dynamics of proteins that are structurally and functionally related. In this study, we present native-state molecular dynamic simulations of four proteins which possess a ubiquitin-like fold. Three of these proteins are thought to have evolved from a common ancestral ubiquitin-like protein and have similarities in their function. A fourth protein, which is structurally homologous but which appears to have a different function, is also studied. Local fluctuations in the native state simulations are analysed, and conserved motions of the C-α backbone atoms are identified in residues which are important for function. In addition, the global dynamics of the proteins are analysed using the essential-dynamics method. This analysis reveals a slightly higher degree of conservation in dynamics for the three proteins which are functionally related. Both the global and local analyses illustrate how nature has optimized and conserved protein motions for specific biological activity within the ubiquitin family.

[1]  J. Gergen,et al.  DNA-binding by Ig-fold proteins , 2001, Nature Structural Biology.

[2]  Valerie Daggett,et al.  Molecular dynamics simulations of hydrophobic collapse of ubiquitin , 1998, Protein science : a publication of the Protein Society.

[3]  H. Berendsen,et al.  Molecular dynamics with coupling to an external bath , 1984 .

[4]  M. Ceruso,et al.  Selective excitation of native fluctuations during thermal unfolding simulations: horse heart cytochrome c as a case study. , 2003, Biophysical journal.

[5]  G. Petsko,et al.  Crystalline ribonuclease A loses function below the dynamical transition at 220 K , 1992, Nature.

[6]  Luigi Vitagliano,et al.  Reversible substrate‐induced domain motions in ribonuclease A , 2002, Proteins.

[7]  L. Nicholson,et al.  Solution structure of ThiS and implications for the evolutionary roots of ubiquitin , 2001, Nature Structural Biology.

[8]  C. Bugg,et al.  Structure of ubiquitin refined at 1.8 A resolution. , 1987, Journal of molecular biology.

[9]  B. Tidor.  Molecular dynamics simulations , 1997, Current Biology.

[10]  L. Vitagliano,et al.  Dynamic properties of the N-terminal swapped dimer of ribonuclease A. , 2004, Biophysical journal.

[11]  H. Berendsen,et al.  Essential dynamics of proteins , 1993, Proteins.

[12]  Jianpeng Ma,et al.  A normal mode analysis of structural plasticity in the biomolecular motor F(1)-ATPase. , 2004, Journal of molecular biology.

[13]  H J Berendsen,et al.  A kinetic model for the internal motions of proteins: Diffusion between multiple harmonic wells , 1999, Proteins.

[14]  S. Jackson,et al.  The folding pathway of ubiquitin from all-atom molecular dynamics simulations. , 2004, Biophysical chemistry.

[15]  A. Amadei,et al.  Mechanics and dynamics of B1 domain of protein G: Role of packing and surface hydrophobic residues , 2008, Protein science : a publication of the Protein Society.

[16]  A. Amadei,et al.  On the convergence of the conformational coordinates basis set obtained by the essential dynamics analysis of proteins' molecular dynamics simulations , 1999, Proteins.

[17]  R. Kaptein,et al.  Structure and Flexibility Adaptation in Nonspecific and Specific Protein-DNA Complexes , 2004, Science.

[18]  Dusanka Janezic,et al.  Harmonic analysis of large systems. I. Methodology , 1995, J. Comput. Chem..

[19]  L. Vitagliano,et al.  Subtle functional collective motions in pancreatic‐like ribonucleases: From ribonuclease A to angiogenin , 2003, Proteins.

[20]  Holger Gohlke,et al.  Change in protein flexibility upon complex formation: Analysis of Ras‐Raf using molecular dynamics and a molecular framework approach , 2004, Proteins.

[21]  H. Berendsen,et al.  Interaction Models for Water in Relation to Protein Hydration , 1981 .

[22]  H. Schindelin,et al.  Crystal structure of molybdopterin synthase and its evolutionary relationship to ubiquitin activation , 2001, Nature Structural Biology.

[23]  R. Jernigan,et al.  Proteins with similar architecture exhibit similar large-scale dynamic behavior. , 2000, Biophysical journal.

[24]  M Bycroft,et al.  The UBX domain: a widespread ubiquitin-like module. , 2001, Journal of molecular biology.

[25]  T. Creighton.  Proteins: Structures and Molecular Properties , 1986 .

[26]  S. Jentsch,et al.  Ubiquitin and its kin: how close are the family ties? , 2000, Trends in cell biology.

[27]  D. van der Spoel,et al.  GROMACS: A message-passing parallel molecular dynamics implementation , 1995 .