以分子動態模擬探討乙醇與溫度對人類溶菌酶結構完整性及相關於造成遺傳系統澱粉樣病變之數種人類溶菌酶突變結構改變的影響

Molecular Dynamics Simulations to Investigate the Effects of Ethanol and Temperature on the Structural Integrity of Human Lysozyme and the Conformational Changes of Several Human Lysozyme Variants Associated with Hereditary Systemic Amyloidosis

吳宜靜(YI-CHING WU)

指導教授 ： 劉宣良

國立臺北科技大學/工程學院/化學工程所/碩士(2006年)

摘要

無資料

關鍵字

分子動態模擬 ； 乙醇 ； 人類溶菌酶類澱粉沉積 ； 疏水區域 ； 突變 ； 二級結構

並列摘要

In this study, molecular dynamics (MD) simulations were conducted to investigate 1) the effects of ethanol and temperature on the structural integrity of human lysozyme and 2) the relationships between several human lysozyme variants and amyloidosis. For the first subject, various 2ns MD simulations in ethanol and water with periodic boundary condition at 300, 400, 500, and 600K were conducted. The results show that ethanol exhibits the ability to stabilize human lysozyme at low temperature, whereas it tends to destabilize this protein at high temperature. It can be attributed to that higher temperatures result in the loss of native structure, leading to the exposure of the interior hydrophobic core. At this stage, ethanol plays a role to destabilize this hydrophobic core due to its lower polarity comparing to water. Such newly formed hydrophobic interactions between the hydrophobic core and ethanol accelerate the unfolding of this protein, starting from the core between the alpha- and beta-domains.
Previous studies have shown that several human lysozyme variants can cause hereditary systemic nonneuropathic amyloidosis, where insoluble beta-stranded fibrils (amyloids) are found in tissues stemming from the aggregation of partially folded intermediates of these variants. For the second subject of this study, we aimed to investigate the structural characteristics of three variants (I56T, D67H, and T70N) in the beta-domain of human lysozyme at elevated temperatures in ethanol and water using MD simulations. Our results show that these variants denature slightly faster than wild-type human lysozyme by losing most of their native secondary structures and developing random transient beta-turns across the whole polypeptide chain. D67H variant tends to decrease the structural stability of the beta-domain due to the destruction of the hydrogen bonding network stabilizing the beta-domain, followed by the distortion and exposure of the interior hydrophobic core. For the I56T variant, the introduction of a hydrophilic residue in the hydrophobic core directly destroys the native contacts in the alpha-beta interface, leading to fast unfolding. Our results are consistent with the previously experimental results suggesting that hydrophobic core at the alpha-beta interface is pivotal in amyloidosis.

並列關鍵字

molecular dynamics simulations ； ethanol ； amyloidosis ； hydrophobic core ； mutation ； secondary structure

參考文獻

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