Flap Dynamics in Pepsin-Like Aspartic Proteases: A Computational Perspective Using Plasmepsin-II and BACE-1 as Model Systems.
Flap Dynamics in Pepsin-Like Aspartic Proteases: A Computational Perspective Using Plasmepsin-II and BACE-1 as Model Systems.
复制标题
DOI：
10.1021/acs.jcim.1c00840
复制
发表时间：
2022-02-28
影响因子：
5.6
通讯作者：
Söderhjelm P
中科院分区：
文献类型：
--
作者：
Bhakat S;Söderhjelm P
β发夹结构的柔韧性在胃酶样天冬氨酸蛋白酶的催化活性和底物摄取中起着关键作用。这些酶中的大多数在结构和序列上都有相似性。在本研究中，我们使用载脂蛋白PLM-II和BACE-1作为模型系统。在蛋白水解酶的载脂蛋白形式中，通过旋转χ1和χ2角，瓣区保守的酪氨酸残基保持在正常和反转状态之间的动态平衡。PLM-II和BACE-1的独立MD模拟仍然停留在正常或反转状态。使用侧链扭转角(酪氨酸的χ1和χ2)作为集合变量的元动力学模拟采样了正常状态和反转状态之间的转换。从质量上讲，预计这两个州的人口数量相等。正常和反转状态分别通过与色氨酸残基和催化天冬氨酸的氢键相互作用来稳定。此外，酪氨酸突变为具有较小侧链的氨基酸，如丙氨酸，降低了瓣的灵活性，导致瓣坍塌(瓣失去灵活性，并保持在特定状态)。这与之前的实验研究是一致的，实验研究表明，丙氨酸的突变会导致胃蛋白酶样天冬氨酸蛋白酶的活性丧失。我们的结果表明，与酪氨酸侧链相关的环翻转是控制大多数胃蛋白酶样天冬氨酸蛋白酶的折叠动力学和结合口袋打开的关键序参数。
The flexibility of β hairpin structure known as the flap plays a key role in catalytic activity and substrate intake in pepsin-like aspartic proteases. Most of these enzymes share structural and sequential similarity. In this study, we have used apo Plm-II and BACE-1 as model systems. In the apo form of the proteases, a conserved tyrosine residue in the flap region remains in a dynamic equilibrium between the normal and flipped states through rotation of the χ1 and χ2 angles. Independent MD simulations of Plm-II and BACE-1 remained stuck either in the normal or flipped state. Metadynamics simulations using side-chain torsion angles (χ1 and χ2 of tyrosine) as collective variables sampled the transition between the normal and flipped states. Qualitatively, the two states were predicted to be equally populated. The normal and flipped states were stabilized by H-bond interactions to a tryptophan residue and to the catalytic aspartate, respectively. Further, mutation of tyrosine to an amino-acid with smaller side-chain, such as alanine, reduced the flexibility of the flap and resulted in a flap collapse (flap loses flexibility and remains stuck in a particular state). This is in accordance with previous experimental studies, which showed that mutation to alanine resulted in loss of activity in pepsin-like aspartic proteases. Our results suggest that the ring flipping associated with the tyrosine side-chain is the key order parameter that governs flap dynamics and opening of the binding pocket in most pepsin-like aspartic proteases.
登录
查看更多内容
影响因子：
5.7
作者：
Gorfe, AA;Caflisch, A
通讯作者：
Caflisch, A
影响因子：
2.4
作者：
GRUBMULLER, H
通讯作者：
GRUBMULLER, H
DOI：
10.1080/07391102.2015.1064831
发表时间：
2016-01-01
影响因子：
4.4
作者：
Kumalo, Hezekiel M.;Bhakat, Soumendranath;Soliman, Mahmoud E.
通讯作者：
Soliman, Mahmoud E.
DOI：
10.1016/j.bbapap.2011.04.008
发表时间：
2012-01
影响因子：
3.2
作者：
Bhaumik, Prasenjit;Gustchina, Alla;Wlodawer, Alexander
通讯作者：
Wlodawer, Alexander
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML