Human　immunodeficiency　virus　type　1　(HIV-1)　integrase　(IN)　is　an　essential　enzyme　in　the　HIV-1　lifecycle　which　aids　the　integration　of　viral　DNA　into　the　host　chromosome.　Recently　synthesized　12-mer　peptide　EBR28,　which　can　strongly　bind　to　IN,　is　one　of　the　most　potential　small　peptide　leading　compounds　inhibiting　IN　binding　with　viral　DNA.　However,　the　binding　mode　between　EBR28　peptide　with　HIV-1　IN　and　the　inhibition　mechanism　remain　uncertain.　In　this　paper,　the　binding　modes　of　EBR28　with　HIV-1　IN　monomer　core　domain　(IN1)　and　dimmer　core　domain　(IN2)　were　investigated　by　using　molecular　docking　and　molecular　dynamics　(MD)　simulation　methods.　The　results　indicated　that　EBR28　bound　to　the　interfaces　of　the　IN1　and　IN2　systems　mainly　through　the　hydrophobic　interactions　with　the　beta　3,　alpha　1　and　alpha　5　regions　of　the　proteins.　The　binding　free　energies　for　IN1　with　a　series　of　EBR28　mutated　peptides　were　calculated　with　the　MM/GBSA　model,　and　the　correlation　between　the　calculated　and　experimental　binding　free　energies　is　very　good　(r=0.88).　Thus,　the　validity　of　the　binding　mode　of　IN1　with　EBR28　was　confirmed.　Based　on　the　binding　modes,　the　inhibition　mechanism　of　EBR28　was　explored　by　analyzing　the　essential　dynamics　(ED),　energy　decomposition　and　the　mobility　of　EBR28　in　the　two　docked　complexes.　The　proposed　inhibition　mechanism　is　represented　that　EBR28　binds　to　the　interface　of　IN1　to　form　the　IN1-EBR28　complex　and　preventes　the　formation　of　IN　dimmer,　finally　leads　to　the　partial　loss　of　binding　potency　for　IN　with　viral　DNA.　All　of　the　above　simulation　results　agree　well　with　experimental　data,　which　provide　us　with　some　helpful　information　for　designing　anti-HIV　small　peptide　drugs.　(C)　2007　Published　by　Elsevier　B.V.