Combining Molecular and Spin Dynamics Simulations with Solid-State NMR: A Case Study of Amphiphilic Lysine–Leucine Repeat Peptide Aggregates
Combining Molecular and Spin Dynamics Simulations with Solid-State NMR: A Case Study of Amphiphilic Lysine–Leucine Repeat Peptide Aggregates
复制标题
将分子和自旋动力学模拟与固态 NMR 相结合：两亲性赖氨酸-亮氨酸重复肽聚集体的案例研究
DOI：
10.1021/acs.jpcb.9b09245
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Drobny, Gary P.
中科院分区：
文献类型：
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作者：
Emani, Prashant S.;Yimer, Yeneneh Y.;Davidowski, Stephen K.;Gebhart, Rachel N.;Ferreira, Helen E.;Kuprov, Ilya;Pfaendtner, Jim;Drobny, Gary P.
解释固态分子系统中的动力学需要表征分子的潜在异质环境背景。特别是，固态核磁共振（ssNMR）数据的分析，以阐明分子动力学（MD）涉及建模的限制整体翻滚的邻居，以及水和缓冲液的浓度。在这种探索的影响运动的因素，我们利用原子的MD轨道的肽聚集体与不同的水化模拟无定形固态环境和预测ssNMR弛豫速率。我们还占自旋扩散多自旋标记（多达19个核）的残留物，偶极耦合网络的几个模型。该框架作为一个通用的方法来确定基本的自旋耦合影响放松，基准MD力场，并揭示了在拥挤的环境中的动态水合依赖。我们证明了先前表征的两亲性14-残基赖氨酸-亮氨酸重复肽LKα14（Ac-LKKLLKLLKKLLKL-c）的方法，其具有α-螺旋二级结构，并且在固态下嘌呤形成亮氨酸掩埋四聚体。我们测量了LKα14疏水核中13 C标记和2 H标记的亮氨酸在多个水化水平下的R1弛豫速率。对9和18四聚体束的研究表明：（a）对于13 C弛豫的非相干分量，最近邻自旋相互作用占主导地位，而1H-1H相互作用的影响很小;（B）对于亮氨酸Cγ-Cδ键，AMBER ff14 SB二面角势垒（“甲基旋转势垒”）必须降低0.7倍以更好地匹配2 H数据;（c）质子驱动的自旋扩散解释了Cβ和Cα核的实验和模拟速率之间的一些差异;和（d）在所有水合作用下，13 C弛豫速率在MD模拟中大多被低估，并且差异确定了在50 ns MD轨迹中可能缺失的运动。
Interpreting dynamics in solid-state molecular systems requires characterization of the potentially heterogeneous environmental contexts of molecules. In particular, the analysis of solid-state nuclear magnetic resonance (ssNMR) data to elucidate molecular dynamics (MD) involves modeling the restriction to overall tumbling by neighbors, as well as the concentrations of water and buffer. In this exploration of the factors that influence motion, we utilize atomistic MD trajectories of peptide aggregates with varying hydration to mimic an amorphous solid-state environment and predict ssNMR relaxation rates. We also account for spin diffusion in multiply spin-labeled (up to 19 nuclei) residues, with several models of dipolar-coupling networks. The framework serves as a general approach to determine essential spin couplings affecting relaxation, benchmark MD force fields, and reveal the hydration dependence of dynamics in a crowded environment. We demonstrate the methodology on a previously characterized amphiphilic 14-residue lysine–leucine repeat peptide, LKα14 (Ac-LKKLLKLLKKLLKL-c), which has an α-helical secondary structure and putatively forms leucine-burying tetramers in the solid state. We measure the R1relaxation rates of uniformly13C-labeled and site-specific2H-labeled leucines in the hydrophobic core of LKα14 at multiple hydration levels. Studies of 9 and 18 tetramer bundles reveal the following: (a) for the incoherent component of13C relaxation, the nearest-neighbor spin interactions dominate, while the1H–1H interactions have minimal impact; (b) the AMBER ff14SB dihedral barriers for the leucine Cγ–Cδbond (“methyl rotation barriers”) must be lowered by a factor of 0.7 to better match the2H data; (c) proton-driven spin diffusion explains some of the discrepancy between experimental and simulated rates for the Cβand Cαnuclei; and (d)13C relaxation rates are mostly underestimated in the MD simulations at all hydrations, and the discrepancies identify likely motions missing in the 50 ns MD trajectories.