Mechanism of the CD2/CD58 complex formation in immune system

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The mechanism of the CD2/CD58 complex formation was investigated by computer simulation. Our purposes of this project are 1) Investigate protein dynamics involved with the complex formation, 2) Estimate contribution from amino acid residues and energy terms by free energy analysis, 3) Investigate the role of CD2/CD58 complex formation in signal transfer. In order to attain the first purpose, a novel method has been developed in order to refine structure and dynamic of proteins in solution by using NMR restraints and relaxation parameters. This method is based on the concept of Jumping-Among-Minima (JAM) model: In this model we assume that protein dynamics consists of two types of motions, intra-substate motion and inter-substate motion. Intra-substate motions, which occur in the time scale of~ 10 psec, are simulated with molecular dynamics calculations with force field energy terms. Inter-substate motions are included by creating an ensemble of structures consistent with the geometric … More NMR restraints. Statistical weights of the conformational substates are determined to reproduce the NMR relaxation parameters. The motions affect primarily the curvature of the slightly concave counter-receptor-binding site and represent transitions between a concave (closed) and flat (open) binding face. By comparing the ensemble of structures in solution to the complex structure with counter receptor CD58, we found that these two types of transitions resemble the change upon counter-receptor binding. To achieve the second purpose, we have developed the REUS (Replica Exchange Umbrella Sampling) to carry out free energy calculation. This method is the combination of the replica exchange method and WHAM (Weighted Histogram Analysis Method). This enables us to estimate binding free energy more accurately. Free energy analysis of various mutations are being carried out but not yet finished. We are planning to continue this kind of calculation to further investigate the signal transfer mechanisms in immune system. Less