計(jì)算方法研究HIV-1蛋白酶及其變異與小分子GRL-0519的相互作用
發(fā)布時(shí)間：2018-10-14 09:16
【摘要】：艾滋病病毒在世界范圍內(nèi)的傳播,嚴(yán)重地威脅到人們的身心健康.HIV-1蛋白酶的殘基變異嚴(yán)重地削弱了藥物的治療效果.為了研究殘基變異D30N、I54M和V82A對蛋白酶結(jié)合抑制劑GRL-0519的影響,本研究進(jìn)行了4個(gè)30 ns的分子動(dòng)力學(xué)(MD)模擬,并采用溶解相互自由能(SIE)方法計(jì)算了蛋白酶和抑制劑的結(jié)合能.計(jì)算結(jié)果表明,極性相互作用不利于變異的蛋白酶結(jié)合抑制劑,而對于野生型的蛋白酶(WT),極性相互作用有微弱的貢獻(xiàn),極性相互作用是殘基變異抗藥性的主要原因,計(jì)算得到的總結(jié)合能與實(shí)驗(yàn)的數(shù)據(jù)一致.為了說明每個(gè)殘基在抗藥性中的貢獻(xiàn),采用分子力場的方法計(jì)算了每一個(gè)殘基與小分子作用的范德華作用能,并分析了抑制劑與蛋白酶形成的氫鍵.范德華作用分析表明,V82A殘基變異對結(jié)合模式的影響較小,相對于WT,D30N有5個(gè)殘基的范德華貢獻(xiàn)差異大于0.4 kcal/mol,I54M殘基變異的蛋白酶有6個(gè)殘基.氫鍵的分析說明,D30N和I54M變異丟失了幾個(gè)氫鍵;范德華作用和氫鍵的分析結(jié)果與SIE的計(jì)算結(jié)果一致.研究結(jié)果為設(shè)計(jì)新的更有效的抗HIV-1蛋白酶變異的抑制劑提供了理論指導(dǎo).
[Abstract]:The spread of HIV in the world seriously threatens people's physical and mental health. The mutation of HIV-1 protease residues seriously weakens the therapeutic effect of drugs. In order to study the effect of residue variant D30NNtI54M and V82A on protease binding inhibitor GRL-0519, four 30 ns molecular dynamics (MD) simulations were carried out, and the binding energies of protease and inhibitor were calculated by means of dissolution mutual free energy (SIE) method. The results showed that the polar interaction was not conducive to the protease binding inhibitor, but had a weak contribution to the polar interaction of the wild type protease (WT), and the polar interaction was the main reason for the resistance of the residue variant. The calculated total binding energy is consistent with the experimental data. In order to explain the contribution of each residue to drug resistance, the van der Waals interaction energy of each residue with small molecules was calculated by molecular force field method, and the hydrogen bond formed between inhibitor and protease was analyzed. Van der Waals interaction analysis showed that the V82A residue variation had little effect on the binding model, and there were 6 residues in the protease with more than 0.4 kcal/mol,I54M residue variation compared with the Van der Waals contribution with 5 residues in WT,D30N. The hydrogen bond analysis shows that several hydrogen bonds are lost in the D30N and I54M mutations, and the results of van der Waals interaction and hydrogen bond analysis are in agreement with the results calculated by SIE. The results provide theoretical guidance for the design of new and more effective inhibitors against HIV-1 protease mutation.
【作者單位】： 德州學(xué)院物理與電子信息學(xué)院;德州學(xué)院山東省生物物理重點(diǎn)實(shí)驗(yàn)室;
【基金】：國家自然科學(xué)基金(11447004,61671107) 山東省自然科學(xué)基金(ZR2014JL006) 山東省泰山學(xué)者基金資助項(xiàng)目~~
【分類號(hào)】：R373
，
本文編號(hào)：2270033
[Abstract]:The spread of HIV in the world seriously threatens people's physical and mental health. The mutation of HIV-1 protease residues seriously weakens the therapeutic effect of drugs. In order to study the effect of residue variant D30NNtI54M and V82A on protease binding inhibitor GRL-0519, four 30 ns molecular dynamics (MD) simulations were carried out, and the binding energies of protease and inhibitor were calculated by means of dissolution mutual free energy (SIE) method. The results showed that the polar interaction was not conducive to the protease binding inhibitor, but had a weak contribution to the polar interaction of the wild type protease (WT), and the polar interaction was the main reason for the resistance of the residue variant. The calculated total binding energy is consistent with the experimental data. In order to explain the contribution of each residue to drug resistance, the van der Waals interaction energy of each residue with small molecules was calculated by molecular force field method, and the hydrogen bond formed between inhibitor and protease was analyzed. Van der Waals interaction analysis showed that the V82A residue variation had little effect on the binding model, and there were 6 residues in the protease with more than 0.4 kcal/mol,I54M residue variation compared with the Van der Waals contribution with 5 residues in WT,D30N. The hydrogen bond analysis shows that several hydrogen bonds are lost in the D30N and I54M mutations, and the results of van der Waals interaction and hydrogen bond analysis are in agreement with the results calculated by SIE. The results provide theoretical guidance for the design of new and more effective inhibitors against HIV-1 protease mutation.
【作者單位】： 德州學(xué)院物理與電子信息學(xué)院;德州學(xué)院山東省生物物理重點(diǎn)實(shí)驗(yàn)室;
【基金】：國家自然科學(xué)基金(11447004,61671107) 山東省自然科學(xué)基金(ZR2014JL006) 山東省泰山學(xué)者基金資助項(xiàng)目~~
【分類號(hào)】：R373
，
本文編號(hào)：2270033
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