Characterize dynamic conformational space of human CCR5 extracellular domain by molecular modeling and molecular dynamics simulation

The chemokine receptor CCR5 is the receptor for several chemokines and major coreceptor for R5 human immunodeficiency virus type-1 strains entry into cell. Three-dimensional models of CCR5 were built by using homology modeling approach and 1 ns molecular dynamics (MD) simulation, because studies of site-directed mutagenesis and chimeric receptors have indicated that the N-terminus (Nt) and extracellular loops (ECLs) of CCR5 are important for ligands binding and viral fusion and entry, special attention was focused on disulfide bond function, conformational flexibility, hydrogen bonding, electrostatic interactions, and solvent-accessible surface area of Nt and ECLs of this protein part. We found that the extracellular segments of CCR5 formed a well-packet globular domain with complex interactions occurred between them in a majority of time of MID simulation, but Nt region could protrude from this domain sometimes. The disulfide bond Cys20-Cys269 is essential in controlling specific orientation of Nt region and maintaining conformational integrity of extracellular domain. RMS comparison analysis between conformers revealed the ECL1 of CCR5 stays relative rigid, whereas the ECL2 and Nt are rather flexible. Solvent-accessible surface area calculations indicated that the charged residues within Nt and ECL2 are often exposed to solvent. Integrating these results with available experimental data, a two-step gp120-CCR5 binding mechanism was proposed. The dynamic interaction of CCR5 extracellular domain with gp120 was emphasized. (C) 2004 Elsevier B.V. All rights reserved.

The effect of human rhythm on packet delivery

In communication networks such as the Internet, the relationship between packet generation rate and time is similar to a rectangle wavefunction due to the rhythm of humans. Thus, we investigate the traffic dynamics on a network with a rectangle wavepacket generation rate. It is found that the critical delivering capacity parameter beta(c) (which separates the congested phase and the free phase) decreases significantly with the duty cycle r of the rectangle wave for package generation. And, in the congested phase, more collective generation of packets (smaller r) is helpful for decreasing the packet aggregation rate. Moreover, it is found that the congested phase can be divided into two regions, i.e., region1 and region2, where the distributions of queue lengths are nonlinear and linear, respectively. Also, the linear expression for the distribution of queue lengths in region2 is obtained analytically. Our work reveals an obvious effect of the rectangle wave on the traffic dynamics and the queue length distribution in the system, which is of essential interest and may provide insights into the designing of work-rest schedules and routing strategies.