MOLECULAR DYNAMICS SIMULATIONS OF BIOLOGICAL MACROMOLECULES

计算生物物理学部分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、小分子结构的从头算分析和分子图形学。这些技术被广泛应用于各种大分子体系。应用于生物医学感兴趣的分子的特定项目使用分子动力学模拟来预测多肽和蛋白质的功能或结构。这些项目包括：-追踪β-内酰胺水解的催化途径这些项目包括：-脂双层凝胶相模拟-研究核酸结构的环境依赖性-建模亮氨酸拉链：螺旋螺旋平行和反平行取向的起源-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理-二氧化碳的分子动力学模拟包括青霉素和头孢菌素在内的β-内酰胺类抗生素的使用受到细菌防御性b-内酰胺酶活性的限制。尽管反应机理已经在实验上得到了很好的研究，但所需部位残基和活性部位残基的具体作用和质子化状态仍然不清楚。本项目使用量子力学和经典处理相结合的方法，研究青霉素G在临床上流行的β-内酰胺酶TEM1中的两种可能的反应机制。这些都是非常大的计算，因为初步工作表明，QM区域必须扩大三倍，以便在研究中包括额外的活性中心残基，因为它们在减少势垒方面的作用或它们参与了质子穿梭机制。目前的研究发现，除了结构上的重要性外，保守残基(S130，K243)还具有催化作用。研究还表明，保守赖氨酸(K73)的质子化状态对决定水解路径至关重要。这项研究区分了两种提出的机制，并证实了如果K73最初被去质子化，质子转移的低能垒。这一点得到了泊松-玻尔兹曼计算的支持，该计算表明，由于邻近的电荷、活性中心的放置和H3α螺旋的附近末端，K73是去质子化的。-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