MOLECULAR DYNAMICS SIMULATIONS OF BIOLOGICAL MACROMOLECULES

计算生物物理部使用几种理论技术研究具有生物学意义的问题：分子动力学、分子力学、建模、小分子结构的从头分析和分子图形学。这些技术应用于各种各样的大分子体系。应用于生物医学分子的特定项目使用分子动力学模拟来预测肽和蛋白质的功能或结构。这些项目包括：-内酰胺水解催化途径的追踪-内酰胺结合的自由能研究-原生和突变vnd/NK-2同源结构域的分子动力学-DNA复合物- C3a过敏毒素和抗体结合位点-人鼻病毒的蛋白质结构稳定和活性-用QM/MM方法模拟腺苷激酶的催化机制- NK/MHC I复合物的分子动力学模拟基础研究正在进行中，以提供更好的理解大分子系统。项目包括：脂质双层凝胶相模拟研究核酸结构的环境依赖性建模亮氨酸拉链：线圈平行与反平行方向的起源蛋白质动力学的环境依赖性肌红蛋白-使用QM/MM方法研究醛糖还原酶的催化机制- ci2的分子动力学模拟- β -内酰胺类抗生素的使用，包括青霉素和头孢菌素，受到细菌防御性b-内酰胺酶活性的限制。虽然实验研究了反应机理，但所需和活性位点残基的具体作用和质子化状态尚不清楚。本项目研究了青霉素- g在TEM-1（临床上普遍存在的β -内酰胺酶）中的两种可能的反应机制，采用混合量子力学和经典治疗。这些是非常大的计算，因为初步的工作表明，QM区域必须扩大三倍，以包括研究中额外的活性位点残基，因为它们在减少障碍或参与质子穿梭机制中的作用。目前的研究已经确定了保守残基（S130, K243）的催化作用，以及它们的结构重要性。该研究还表明，保守赖氨酸（K73）的质子化状态对确定水解途径至关重要。该研究区分了两种提出的机制，并证实了如果K73最初去质子化，质子转移的低能量障碍。泊松-玻尔兹曼计算结果支持了这一观点。泊松-玻尔兹曼计算结果表明，K73由于邻近的电荷、活性位点的放置和H3 α螺旋的附近末端而去质子化。-分子动力学、模拟、机理、理论、分子图形学、量子力学

The Computational Biophysics Section studies problems of biological significance using several theoretical techniques: molecular dynamics, molecular mechanics, modeling, abinitio analysis of small molecule structure, and molecular graphics. These techniques are applied to a wide variety of macromolecular systems. Specific projects applied to molecules of biomedical interest uses molecular dynamics simulations to predict function or structures of peptides and proteins. Such projects include:- Tracing the catalytic pathway of beta-lactam hydrolysis- Free energy studies of beta-lactam binding- Molecular dynamics of native and mutant vnd/NK-2 homeodomain--DNA complexes- C3a anaphylatoxin and antibody binding sites- Protein structure stabilization and activity in human rhinovirus- Modeling the catalytic mechanism of adenosine kinase with QM/MM methods- Molecular dynamics simulation on NK/MHC I complex Basic research is underway to provide a better understanding of macromolecular systems. The projects include studies of:- Lipid bilayer gel phase simulations- Investigating the environmental dependence of nucleic acid structure- Modeling leucine zippers: Origins of parallel vs. antiparallel orientation of coiledcoils- Environmental dependence of protein dynamics: Myoglobin- The study of the catalytic mechanism of aldose reductase using QM/MM methods- Molecular dynamics simulations of CI2The use of the beta-lactam family of antibiotics, including penicillin and cephalosporin, is limited by the activity of the bacterias defensive b-lactamases. Although, the reaction mechanism has been well studied experimentally, the specific role and protonation states of the required and active site residues are still unclear. This project investigates the two suggested reaction mechanisms of Penicillin-G in TEM-1, a clinically prevalent beta-lactamase, using a hybrid quantum mechanical and classical treatment. These are very large calculations since preliminary work suggested that the QM region had to be expanded three times to include additional active site residues in the study because of their role in reducing barriers or their participation in a proton-shuttle mechanism. The current study has identified catalytic roles for conserved residues (S130, K243) in addition to their structural importance. The study also has shown that the protonation state of a conserved lysine (K73) is critical to determining the hydrolytic path. The study differentiates between two proposed mechanisms and confirms the low energy barriers to proton transfer if K73 is initially deprotonated. This is supported by Poisson-Boltzmann calculations which suggest that K73 is deprotonated due to adjacent charges, active site placement and the nearby terminus of the H3 alpha helix. - molecular dynamics, simulation, mechanism, theory, molecular graphics, quantum mechanics