A simple lattice model that captures protein folding, aggregation and amyloid formation.
A simple lattice model that captures protein folding, aggregation and amyloid formation.
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DOI：
10.1371/journal.pone.0085185
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Frenkel D
中科院分区：
文献类型：
--
作者：
Abeln S;Vendruscolo M;Dobson CM;Frenkel D
许多蛋白质从其功能性可溶性状态转化为淀粉样原纤维的能力可归因于分子间β链的形成。这种淀粉样蛋白的形成与阿尔茨海默病和帕金森病等神经退行性疾病有关。分子模型可以在提供洞察使蛋白质易于形成纤维的因素方面发挥关键作用。然而，完全原子模型在计算上过于昂贵，无法捕获与纤维形成相关的长度和时间尺度。由于形成原纤维的能力是规律而不是例外，因此可以从捕获与淀粉样蛋白形成相关的关键一般特征的粗粒度模型的研究中获得许多见解。在这里，我们提出了一个简单的晶格模型，可以捕获蛋白质折叠和β链形成。与标准晶格模型不同，该模型明确地结合了氢键的形成和侧链的方向性。该模型的简单性使得研究折叠、无定形聚集和纤维形成之间的相互作用在计算上可行，并保持了经典晶格模型高特异性模拟蛋白质折叠的能力。在我们的模型中，折叠的蛋白质包含类似于自然发生的β -片的结构，具有交替的极性和疏水氨基酸。此外，具有分子间交叉-链构象的原纤维可以由多个短的疏水肽序列自发形成。折叠结构和原纤维中氢键的形成都强烈依赖于氨基酸序列，这表明单独的氢键相互作用不足以引发β片的形成。这一结果与实验观察结果一致，即β片和淀粉样蛋白的形成强烈依赖于序列，疏水序列更容易形成这种结构。我们的模型应该为系统研究导致淀粉样蛋白形成的因素之间的相互作用开辟道路。
The ability of many proteins to convert from their functional soluble state to amyloid fibrils can be attributed to inter-molecular beta strand formation. Such amyloid formation is associated with neurodegenerative disorders like Alzheimer's and Parkinson's. Molecular modelling can play a key role in providing insight into the factors that make proteins prone to fibril formation. However, fully atomistic models are computationally too expensive to capture the length and time scales associated with fibril formation. As the ability to form fibrils is the rule rather than the exception, much insight can be gained from the study of coarse-grained models that capture the key generic features associated with amyloid formation. Here we present a simple lattice model that can capture both protein folding and beta strand formation. Unlike standard lattice models, this model explicitly incorporates the formation of hydrogen bonds and the directionality of side chains. The simplicity of our model makes it computationally feasible to investigate the interplay between folding, amorphous aggregation and fibril formation, and maintains the capability of classic lattice models to simulate protein folding with high specificity. In our model, the folded proteins contain structures that resemble naturally occurring beta-sheets, with alternating polar and hydrophobic amino acids. Moreover, fibrils with intermolecular cross-beta strand conformations can be formed spontaneously out of multiple short hydrophobic peptide sequences. Both the formation of hydrogen bonds in folded structures and in fibrils is strongly dependent on the amino acid sequence, indicating that hydrogen-bonding interactions alone are not strong enough to initiate the formation of beta sheets. This result agrees with experimental observations that beta sheet and amyloid formation is strongly sequence dependent, with hydrophobic sequences being more prone to form such structures. Our model should open the way to a systematic study of the interplay between the factors that lead to amyloid formation.
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DOI：
10.1080/01621459.1995.10476590
发表时间：
1995-09-01
影响因子：
3.7
作者：
GEYER, CJ;THOMPSON, EA
通讯作者：
THOMPSON, EA
DOI：
10.1073/pnas.0402525101
发表时间：
2004-05-25
影响因子：
11.1
作者：
Hoang, TX;Trovato, A;Maritan, A
通讯作者：
Maritan, A
影响因子：
15
作者：
Naganathan, AN;Sanchez-Ruiz, JM;Muñoz, V
通讯作者：
Muñoz, V
影响因子：
5.6
作者：
PRIVALOV, PL;TIKTOPULO, EI;KHECHINASHVILI, NN
通讯作者：
KHECHINASHVILI, NN
影响因子：
5.6
作者：
SALI, A;SHAKHNOVICH, E;KARPLUS, M
通讯作者：
KARPLUS, M