Biomedical subjects

C Paul Barrett

Publications and source records attributed to C Paul Barrett.

4 recordsLinked to original sources

PubMed2006

Computational analyses of the surface properties of protein-protein interfaces.

Several potential applications of structural biology depend on discovering how one macromolecule might recognize a partner. Experiment remains the best way to answer this question, but computational tools can contribute where this fails. In such cases, structures may be studied to identify patches of exposed residues that have properties common to interaction surfaces and the locations of these patches can serve as the basis for further modelling or for further experimentation. To date, interaction surfaces have been proposed on the basis of unusual physical properties, unusual propensities for particular amino-acid types or an unusually high level of sequence conservation. Using the CXXSurface toolkit, developed as a part of the CCP4MG program, a suite of tools to analyse the properties of surfaces and their interfaces in complexes has been prepared and applied. These tools have enabled the rapid analysis of known complexes to evaluate the distribution of (i) hydrophobicity, (ii) electrostatic complementarity and (iii) sequence conservation in authentic complexes, so as to assess the extent to which these properties may be useful indicators of probable biological function.

Computational Biology↗

PubMed2005

Dynamite extended: two new services to simplify protein dynamic analysis.

We describe two additional services now available as part of the previously described Dynamite protein dynamics web service. Dynatraj provides principle component analysis and visualization of modes of motion for a user's own ensemble of protein structures, e.g. from Molecular Dynamics, NMR or experimental ensembles. Dynapocket predicts probable configurations of a protein pocket from a single known structure. Both have been provided in response to requests from users for additional functionality from the Dynamite server. Like Dynamite, both are available free of charge to all users.

Algorithms↗

PubMed2005

Molecular motions of human cyclin-dependent kinase 2.

We present a comprehensive description of the dynamic behavior of CDK2 in complex with cyclin A, arrived at by analysis of a total of 0.25 micros of solvated molecular dynamics trajectories and 42 deposited CDK2 structures, and refined using other protein simulation algorithms. The CDK2-cyclin A dimer is a dynamic complex of 6 subdomains. Thermal motions are dominated by a relative twisting of the two monomers. The predominant motion within CDK2 is a "breathing" of the N-terminal and C-terminal lobes. The N-terminal lobe of cyclin A is tightly linked to the "PSTAIRE" helix of CDK2 to provide a rigid nucleus to the complex. By contrast, the "CDK-insert" region (residues 219-251) sometimes becomes highly mobile, a behavior that is observed in crystallographic analyses of CDK2 structures and that may relate to its role in recognizing diverse binding partners. We find that the three arginines that anchor phosphothreonine 160 of fully active CDK2 do not contribute equally to structural stabilization. This observation is supported by a survey of protein kinase sequences. We have also explored the physical basis of the role of the phosphate moiety in signaling by artificially modifying the charge of phosphothreonine 160 in molecular dynamics simulations. We find that phosphothreonine binding involves an active process of attraction in which both the receptor site (the arginine triad), and the phosphothreonine have a higher charge than is required to maintain an active conformation once formed. We have deposited our dynamics data to aid protein kinase inhibitor design.

Adenosine Triphosphate↗

PubMed2004

Dynamite: a simple way to gain insight into protein motions.

A public web-based facility to infer, analyse and graphically represent the likely modes of a protein motion, starting from a static structure, is presented. This facility is based on the use of CONCOORD to generate an ensemble of feasible protein structures that are subsequently analysed by principal component analysis to identify probable concerted motions. The user is returned the ensemble of feasible structures, together with associated analyses, including animations and graphical representations of both the principal component of the ensemble covariance and indicators of strongly correlated pairwise atomic motions. Whilst users are warned that completely reliable inferences about protein motion may be beyond even substantially more rigorous tools for exploring configurational space, it is hoped that the service will allow a much wider community to benefit from the insights that simple dynamic data may offer.

Algorithms↗