左旋苯丙胺(又称左苯丙胺,RAT)在临床上被用于治疗多种病症,作用在中枢神经细胞多巴胺受体上,同时它具有依赖性和成瘾性。为了探讨RAT被用作药物的药理和成瘾机制,本文用分子模拟获得RAT与多巴胺第三受体(D_3R)复合蛋白优化结构,并且采...左旋苯丙胺(又称左苯丙胺,RAT)在临床上被用于治疗多种病症,作用在中枢神经细胞多巴胺受体上,同时它具有依赖性和成瘾性。为了探讨RAT被用作药物的药理和成瘾机制,本文用分子模拟获得RAT与多巴胺第三受体(D_3R)复合蛋白优化结构,并且采用伞形样本平均力势(PMF)方法和卵磷脂脂质分子模拟生物膜,采用分子动力学模拟获得RAT在D_3R结构中分子通道运动轨迹和自由能变化。RAT通过D_3R结构中的功能分子通道,朝细胞外方向传输运动的自由能变化为91.4 k J?mol^(-1)。RAT通过D_3R结构中的保护分子通道,朝细胞双层膜方向传输运动的自由能变化为117.7 k J?mol^(-1)。自由能数值表明RAT分子更容易通过D_3R结构中的功能分子通道,发挥其功能作用,增大功能多巴胺分子的释放,导致包括依赖性和成瘾性多种功能效果。研究结果证明RAT被用作药物的药理和成瘾机制与它在多巴胺受体中的分子通道上传输动力学和机制有密切关联。展开更多
Based on the crystal structure of the vitamin B12 transporter protein of Escherichia coli(BtuCD) a system consisting of the BtuCD transmembrane domain(BtuC) and the palmitoyloleoyl phosphatidylcholine(POPC) lipid bila...Based on the crystal structure of the vitamin B12 transporter protein of Escherichia coli(BtuCD) a system consisting of the BtuCD transmembrane domain(BtuC) and the palmitoyloleoyl phosphatidylcholine(POPC) lipid bilayer was constructed in silica,and a more-than-57-nanosecond molecular dynamics(MD) simulation was performed on it to reveal the intrinsic functional motions of BtuC.The results showed that a stable protein-lipid bilayer was obtained and the POPC lipid bilayer was able to adjust its thickness to match the embedded BtuC which underwent relatively complicated motions.These results may help to understand the mechanism of transmembrane substrate transport at the atomic level.展开更多
文摘左旋苯丙胺(又称左苯丙胺,RAT)在临床上被用于治疗多种病症,作用在中枢神经细胞多巴胺受体上,同时它具有依赖性和成瘾性。为了探讨RAT被用作药物的药理和成瘾机制,本文用分子模拟获得RAT与多巴胺第三受体(D_3R)复合蛋白优化结构,并且采用伞形样本平均力势(PMF)方法和卵磷脂脂质分子模拟生物膜,采用分子动力学模拟获得RAT在D_3R结构中分子通道运动轨迹和自由能变化。RAT通过D_3R结构中的功能分子通道,朝细胞外方向传输运动的自由能变化为91.4 k J?mol^(-1)。RAT通过D_3R结构中的保护分子通道,朝细胞双层膜方向传输运动的自由能变化为117.7 k J?mol^(-1)。自由能数值表明RAT分子更容易通过D_3R结构中的功能分子通道,发挥其功能作用,增大功能多巴胺分子的释放,导致包括依赖性和成瘾性多种功能效果。研究结果证明RAT被用作药物的药理和成瘾机制与它在多巴胺受体中的分子通道上传输动力学和机制有密切关联。
基金supported by the National Natural Science Foundation of China (Grant Nos 20773006 and 30670497)the Beijing Natural Science Foun-dation (Grant Nos 7082006 and 5072002)the Specialized Research Fund for the Doctoral Program of Higher Education (Grant No 200800050003)
文摘Based on the crystal structure of the vitamin B12 transporter protein of Escherichia coli(BtuCD) a system consisting of the BtuCD transmembrane domain(BtuC) and the palmitoyloleoyl phosphatidylcholine(POPC) lipid bilayer was constructed in silica,and a more-than-57-nanosecond molecular dynamics(MD) simulation was performed on it to reveal the intrinsic functional motions of BtuC.The results showed that a stable protein-lipid bilayer was obtained and the POPC lipid bilayer was able to adjust its thickness to match the embedded BtuC which underwent relatively complicated motions.These results may help to understand the mechanism of transmembrane substrate transport at the atomic level.
