A molecular dynamics model of HIV-1 reverse transcriptase complexed with DNA: Comparison with experimental structures

We have built a molecular dynamics model for human immunodeficiency virus ( HIV-1) reverse transcriptase (RT) complexed with a 19/18-mer template/prime r by combining the structural information of a low resolution crystal struc ture of a HIV-1 RT/DNA complex (1hmi) with that of a high resolution crysta l structure of unliganded HIV-1 RT (1rtj). The process involved slow forcin g of the alpha -carbons of 1rtj onto those of 1hmi using constrained MD sim ulations, while immersing the protein in aqueous solution. A similar techni que was used to build the bent all-atom DNA duplex, which was then docked i nto the modeled protein. The resulting model complex was refined using mole cular dynamics simulation with the Particle-mesh Ewald method employed to a ccommodate long-range electrostatic interactions. New parameters of the Amb er force field that affect DNA twist are tested and largely validated. The model has been used successfully to explain the results of vertical scannin g mutagenesis of residue 266 (Trp266). Recently, the low resolution crystal structure of the HIV-1 RT/DNA complex has been refined to a 2.8 Angstrom r esolution (2hmi) and a crystal structure of a HIV-1/RT/dTTP ternary complex has been determined at 3.2 Angstrom resolution (1rtd). A detailed structur al comparison of the prior model structure and the two experimental structu res becomes possible. Overall, the three structures share many similarities . The root mean square deviations of the alpha -carbons for the individual subdomains among the three structures are within the same ranges. The secon dary structure assignments in the three structures are nearly identical. Ke y protein-DNA contacts such as those in the region of the primer grip are a lso similar in the three structures.