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Virtual Issue on Fast Dynamics and Function of Biomolecules
The Journal of Physical Chemistry Letters ( IF 5.7 ) Pub Date : 2023-05-25 , DOI: 10.1021/acs.jpclett.3c01122
Valeria Conti Nibali 1 , Alessandro Paciaroni 2
Affiliation  

Cellular functions are governed by a myriad of processes that typically occur through multiple steps, spanning an astonishingly wide time-window from femtoseconds to seconds. This complexity is a reflection of the highly complex structural properties of biomolecules. Despite a great deal of knowledge about these properties being available nowadays, through both experiments (X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy) and deep-learning algorithms (e.g., AlphaFold2, RoseTTAFold in the case of proteins), much less is understood about the dynamic behavior of biomolecules. Particularly, it is becoming increasingly clear that many cellular functions, including those that appear to occur at slower characteristic times, rely on ultrafast and fast processes that happen at the molecular scale within the femtosecond to nanosecond time-window. The question of whether and how ultrafast and fast dynamics are directly related to key biological processes has been the focus of a number of papers published in The Journal of Physical Chemistry Letters over the past two years (2021–2022). The photosynthetic machinery of plants and bacteria, and the way specific fast motions are able to modulate the interplay of its distinct components, has been at the center of investigations based on ultrafast and fast spectroscopies and theoretical calculations. The role played by fast dynamics in energy-dependent feedback deexcitation quenching (qE) is the focus of a study performed by Camargo et al. (1) by picosecond time-resolved photoluminescence and femtosecond transient absorption spectroscopies. qE is one of the response mechanisms underlying nonphotochemical quenching, a complex process that mitigates photodamage from excessive light intensity in plants and algae. The fast dynamics of the light-harvesting complex stress-related 3 (LHCSR3) protein from a bacterial organism is finely dissected, and the pH-dependent quenching mechanism is found to be composed of multiple dynamic contributions triggered by different amino acids. New clues on the very much debated role of electronic/vibrational coherences in the electronic energy transfer (EET) mechanisms in photosynthetic protein complexes are reported by Kim et al. (2) By using synchronized dual-mode-locked laser-based 2-dimensional electronic spectroscopy (SM-2DES) on a bacterial light-harvesting complex II (LHC2), they find that the EET between the two aggregate components of LHC2 is modulated by a low-frequency vibrational mode of the exciton donor. On these bases it is suggested that the energy transfer dynamics are affected by this vibration, via a modulation of the donor transition density. The intricate operational principles of the photosystem II supercomplex (PSII-SC) can be disclosed only by deeply understanding the mechanisms by which the excitation energy flows within and between its different subunits. Along this line, the paper from Do et al. (3) addresses the ultrafast EET in the asymmetric and native complex pentamer LHCII(M)–CP29–CP24 as opposed to LHCII trimers. Ultrafast two-dimensional electronic spectroscopy (2DES) is employed to reveal that the former exhibits faster energy equilibrations in the intermediate levels, and consequently accelerated effective dynamics, than the latter. The origin of this different dynamic behavior is ascribed to the structural change of LHCII(M) in the bigger assembly thanks to high-level structure-based calculations, including intramolecular vibronic transitions. A similar topic pertains to the biological activity of photoreceptors which can be comprehended only once the dynamic fast mechanisms underlying such a process are clarified. Asido et al. (4) apply broadband time-resolved UV/vis spectroscopy and hybrid quantum mechanics/molecular mechanics calculations to characterize the near UV absorption features of the light-driven sodium pump rhodopsin KR2. A close relationship is shown between the chromophore configuration changes, i.e., the all-trans to 13-cis isomerization of retinal and the reisomerization to all-trans, and the induced absorption in the near-UV in the femtosecond up to the millisecond time scale. Further details on the photoisomerization mechanism are provided by Kusochek et al., (5) who investigate the excited state dynamics of KR2 by using MD simulations and QM/MM modeling. Calculations of the vibronic band shapes for various conformations of the protonated Schiff-based retinal (PSBR) shed light on the relationship between the structure of the retinal-binding site and the vibrational modes while also proving that the protein environment alters the vibrational modes that are active upon photoexcitation, facilitating photoisomerization. Photocontrollable proteins/peptides are also being employed to investigate the dynamical aspects underlying protein/ligand binding mechanisms, a crucial topic in protein biochemistry and biophysics. Jankovic et al. (6) have studied the phototriggered unbinding of the intrinsically disordered S peptide from the RNase S complex by means of transient IR spectroscopy. Focusing on the fast dynamics in the sequence of events during peptide unbinding, the authors reveal one event occurring in the time window <100 ps, attributed to the heat dissipated upon isomerization of the photoswitch and another one on the nanosecond time scale, ascribed to the unfolding of the helical structure of the S peptide. Fast dynamical processes are also at the basis of the relaxations of nucleic acid excited states, a topic of particular relevance since it is related to the molecular mechanisms underlying photodamage of the genetic code. Lizondo-Aranda et al. (7) combine ultrafast time-resolved fluorescence spectroscopy and quantum mechanical calculations to investigate how the photoactivated dynamics of the cytidine etheno adduct εdC is altered with respect to that of the canonical dC due to the presence of an extra heterocycle. The mutagenic nucleobase εdC, which is present as an endogeneous DNA lesion in human tissues, shows a decreased efficiency of the nonradiative deactivation of the emissive state, with the consequent lengthening of the excited state lifetime. These findings suggest that εdC may be an internal DNA photosensitizer. One of the few studies on the fluorescence dynamics of RNA has been performed by Chan et al. (8) on a homopolymeric adenine·uracil duplex adopting the A-form structure. By exploiting broadband ultrafast time-resolved fluorescence, the electronically excited RNA is found to deactivate through a dual time-scale proton-transfer mechanism, with the participation of a nanosecond high-energy excitonic state. It is proposed that stacking, pairing, and local hydration environment specific to the duplex A-form conformation are the factors contributing to this behavior, which is quite distinct from that of DNA. The relationship between fast dynamics and allostery in proteins is still elusive. By exploiting time-resolved infrared and UV/vis spectroscopy Bozovic et al. (9) study a photoswitching triggered allosteric transition in a variant of the single-domain PDZ3 protein. The transition is found to occur within a characteristic time scale of 200 ns, while a shorter 4 ns time scale for the unfolding of the allosteric element, an auxiliary helix at the C-terminus (α3), is needed. The same transition is modeled via nonequilibrium molecular dynamics simulations by Ali et al. (10) that are able to unravel the details of the underlying molecular mechanisms at the basis of the allosteric communication. The 5 ns time scale is associated with the stretching of the α3-helix, while the 300 ns time scale is related to the reordering of a network of contacts connecting the allosteric element to the core of the protein, which move in a concerted manner. Complementary to time-resolved techniques, neutron scattering (NS) spectroscopy allows one to explore thermal fluctuations of biomolecules. Cisse et al. (11) propose an original method, based on the use of NS spectrometers with different energy resolutions (i.e., accessible time scales), to single out the internal fast dynamics of Apolipoprotein B-100 of the protein–detergent complex signal. Before concluding this overview of case studies, one cannot fail to mention the dynamic coupling between proteins and their hydration water which is particularly effective in the THz region. This coupling is thought to play a crucial role in activating/modulating the protein dynamics required for biological activity. By employing NS spectroscopy, Yamamoto et al. (12) find that only the unfreezable component of protein hydration water is coupled with the protein dynamics and thus contributes to their activation. Macro et al. (13) investigate the role of protein–water dynamical coupling for the folding of substrate proteins by means of site-specific tryptophanyl mutagenesis as an intrinsic optical probe with femtosecond resolution and molecular dynamics simulations on the GroEL protein. They observe a unique hydration pattern, i.e., a slowdown of the water dynamics from the apical to the equatorial domain of the protein cavity, which suggests that the GroEL mechanism for substrate protein folding is water-mediated. A mechanistic description for the gating for the principal water channel in the brain, aquaporin-4, is proposed by Wei et al. (14) in terms of a cavitation-mediated model. Molecular dynamics simulations show that shockwaves close the channel, while the subsequent jet from bubble collapse opens with an expansion dynamics of secondary helix structures on a short time scale of the order of tens of picoseconds. Pyne and Mitra (15) focus on the role played by protein hydration changes during the liquid–liquid phase separation (LLPS) process of lysozyme in the presence of excipients, carrying out attenuated total reflection (ATR)-FTIR spectroscopy in the THz frequency region (1.5–21 THz). Since the hydration dynamics gets altered during the LLPS, being correlated with the alteration of the protein conformation and with the nature of the excipient, such hydration change could thus serve as a marker of the process. On the other hand, solvent-free/waterless liquid proteins, obtained upon almost complete removal of water from assemblies of proteins enclosed in a corona of polymer surfactant (PS), are also attracting great interest, thanks to their unique properties (high thermal stability, extension of the operation temperature range) and being a good model for crowded biological systems. By using complementary time-resolved fluorescence techniques, Kistwal et al. (16) show that the slow dynamics, considered as a signature of biological water, is also found in waterless PS-complexes and attribute them to the dynamics of the proteins and of the PS chains in the environment of the fluorophore. As showcased in this Virtual Issue, a multitude of intricate biological systems require a thorough comprehension of the fast dynamics underlying the processes they are involved in. Significant challenges persist, as experiments and simulations still fall short in replicating biological environments entirely. However, the advancements in experimental and computational methods achieved in recent years, and which are still ongoing, have the potential to fuel a much closer examination of the behavior of biological systems in actual physiological settings. This article references 16 other publications. This article has not yet been cited by other publications. This article references 16 other publications.

中文翻译:

生物分子快速动力学和功能的虚拟问题

细胞功能由无数过程控制,这些过程通常通过多个步骤发生,跨越从飞秒到秒的惊人宽时间窗。这种复杂性反映了生物分子高度复杂的结构特性。尽管现在可以通过实验(X 射线晶体学、核磁共振光谱学和低温电子显微镜)和深度学习算法(例如,蛋白质的 AlphaFold2、RoseTTAFold)获得大量关于这些特性的知识, 对生物分子的动态行为了解得更少。特别是,越来越清楚的是,许多细胞功能,包括那些似乎发生在较慢特征时间的功能,依赖于飞秒到纳秒时间窗内分子尺度上发生的超快和快速过程。超快和快动力学是否以及如何与关键生物过程直接相关的问题一直是发表在物理化学通讯杂志在过去两年(2021-2022 年)。植物和细菌的光合作用机制,以及特定快速运动能够调节其不同成分相互作用的方式,一直是基于超快和快速光谱学和理论计算的研究中心。Camargo 等人进行的一项研究的重点是快速动力学在能量依赖性反馈失激猝灭 (qE) 中所起的作用。(1) 通过皮秒时间分辨光致发光和飞秒瞬态吸收光谱。qE 是非光化学猝灭的响应机制之一,非光化学猝灭是一种复杂的过程,可减轻植物和藻类因过度光照强度造成的光损伤。来自细菌有机体的光捕获复合应激相关 3 (LHCSR3) 蛋白的快速动力学被精细剖析,发现 pH 依赖性猝灭机制由不同氨基酸触发的多种动态贡献组成。Kim 等人报道了关于电子/振动相干在光合蛋白复合物中电子能量转移 (EET) 机制中备受争议的作用的新线索。(2) 通过在细菌光捕获复合体 II (LHC2) 上使用基于同步双锁模激光的二维电子光谱 (SM-2DES),他们发现 LHC2 的两个聚集体成分之间的 EET 被调制通过激子供体的低频振动模式。在这些基础上,表明能量转移动力学受这种振动的影响,通过对供体跃迁密度的调制。只有深入了解激发能量在其不同亚基内部和之间流动的机制,才能揭示光系统 II 超复合物 (PSII-SC) 的复杂操作原理。沿着这条线,Do 等人的论文。(3) 解决了与 LHCII 三聚体相反的不对称和天然复杂五聚体 LHCII(M)–CP29–CP24 中的超快 EET。采用超快二维电子能谱 (2DES) 揭示前者在中间能级表现出更快的能量平衡,因此比后者加速了有效动力学。这种不同的动态行为的起源归因于 LHCII(M) 在更大组件中的结构变化,这要归功于基于高级结构的计算,包括分子内电子振动跃迁。一个类似的话题涉及光感受器的生物活动,只有弄清楚这种过程背后的动态快速机制才能理解。阿西多等人。(4) 应用宽带时间分辨紫外/可见光谱和混合量子力学/分子力学计算来表征光驱动钠泵视紫红质 KR2 的近紫外吸收特征。发色团构型变化之间显示出密切的关系,即视网膜的全反式到 13-顺式异构化和再异构化到全反式,以及飞秒到毫秒时间尺度的近紫外诱导吸收. Kusochek 等人 (5) 提供了有关光致异构化机制的更多详细信息,他们使用 MD 模拟和 QM/MM 建模研究了 KR2 的激发态动力学。质子化席夫视网膜 (PSBR) 的各种构象的电子振动带形状的计算揭示了视网膜结合位点的结构与振动模式之间的关系,同时也证明了蛋白质环境改变了振动模式在光激发时活跃,促进光异构化。光控蛋白质/肽也被用于研究蛋白质/配体结合机制的动力学方面,这是蛋白质生物化学和生物物理学的一个重要课题。扬科维奇等。(6) 通过瞬态红外光谱研究了 RNase S 复合物中固有无序 S 肽的光触发解结合。关注肽解结合过程中事件序列的快速动态,作者揭示了一个事件发生在 <100 ps 的时间窗内,归因于光开关异构化时的热量消散,另一个事件发生在纳秒时间尺度上,归因于 S 肽螺旋结构的展开。快速动力学过程也是核酸激发态松弛的基础,这是一个特别相关的主题,因为它与遗传密码光损伤的分子机制有关。Lizondo-Aranda 等人。(7) 结合超快时间分辨荧光光谱和量子力学计算,研究胞苷乙烯基加合物 εdC 的光活化动力学如何因额外杂环的存在而相对于规范 dC 发生变化。诱变核碱基 εdC,它作为人体组织中的内源性 DNA 损伤存在,表明发射态的非辐射失活效率降低,随之而来的是激发态寿命的延长。这些发现表明 εdC 可能是一种内部 DNA 光敏剂。Chan 等人对 RNA 的荧光动力学进行了为数不多的研究之一。(8)采用A型结构的均聚腺嘌呤·尿嘧啶双链体。通过利用宽带超快时间分辨荧光,发现电子激发的 RNA 通过双重时间尺度质子转移机制失活,纳秒高能激子态参与。有人提出,双工 A 型构象特有的堆叠、配对和局部水合环境是导致这种行为的因素,这与 DNA 截然不同。蛋白质中快速动力学和变构之间的关系仍然难以捉摸。通过利用时间分辨红外和紫外/可见光谱,Bozovic 等人。(9) 研究光开关触发单域 PDZ3 蛋白变体中的变构转变。发现转变发生在 200 ns 的特征时间尺度内,而变构元素的展开需要更短的 4 ns 时间尺度,即 C 末端的辅助螺旋 (α3)。Ali 等人通过非平衡分子动力学模拟模拟了相同的转变。(10) 能够在变构通信的基础上揭示潜在分子机制的细节。5 ns 时间尺度与 α3-螺旋的拉伸有关,而 300 ns 的时间尺度与连接变构元件和蛋白质核心的接触网络的重新排序有关,这些接触网络以一致的方式移动。作为时间分辨技术的补充,中子散射 (NS) 光谱学允许人们探索生物分子的热波动。西塞等人。(11) 提出了一种原始方法,基于使用具有不同能量分辨率(即,可访问的时间尺度)的 NS 光谱仪,以挑出蛋白质 - 洗涤剂复合信号的载脂蛋白 B-100 的内部快速动力学。在结束案例研究概述之前,不能不提到蛋白质与其水合水之间的动态耦合,这在太赫兹区域特别有效。这种偶联被认为在激活/调节生物活性所需的蛋白质动力学方面起着至关重要的作用。通过使用 NS 光谱学,Yamamoto 等人。(12) 发现只有蛋白质水合水的不可冻结成分与蛋白质动力学相结合,从而有助于它们的活化。宏观等。(13) 通过定点色氨酸诱变研究蛋白质-水动力学耦合对底物蛋白折叠的作用,作为具有飞秒分辨率的内在光学探针和 GroEL 蛋白的分子动力学模拟。他们观察到一种独特的水合模式,即从顶端到蛋白质空腔赤道区域的水动力学减慢,这表明底物蛋白质折叠的 GroEL 机制是水介导的。Wei 等人提出了大脑中主要水通道 aquaporin-4 门控的机制描述。(14)就空化介导的模型而言。分子动力学模拟表明,冲击波关闭通道,而随后气泡破裂产生的射流随着二级螺旋结构的膨胀动力学在数十皮秒量级的短时间尺度上打开。Pyne 和 Mitra (15) 重点研究了溶菌酶在赋形剂存在下的液-液相分离 (LLPS) 过程中蛋白质水合变化所起的作用,在太赫兹频率区域进行了衰减全反射 (ATR)-FTIR 光谱分析(1.5–21 太赫兹)。由于水合动力学在 LLPS 期间发生改变,与蛋白质构象的改变和赋形剂的性质相关,因此,这种水合变化可以作为该过程的标志。另一方面,无溶剂/无水液体蛋白质是从包裹在聚合物表面活性剂 (PS) 电晕中的蛋白质组件中几乎完全去除水分后获得的,由于其独特的性质(高热稳定性),也引起了极大的兴趣, 扩展操作温度范围) 并成为拥挤生物系统的良好模型。通过使用互补时间分辨荧光技术,Kistwal 等人。(16) 表明,被认为是生物水特征的慢动力学也存在于无水 PS 复合物中,并将它们归因于荧光团环境中蛋白质和 PS 链的动力学。如本虚拟问题所示,许多复杂的生物系统需要对它们所涉及的过程背后的快速动力学有透彻的理解。重大挑战仍然存在,因为实验和模拟在完全复制生物环境方面仍然存在不足。然而,近年来在实验和计算方法方面取得的进步仍在进行中,有可能推动对实际生理环境中生物系统行为的更仔细检查。本文引用了 16 篇其他出版物。这篇文章尚未被其他出版物引用。本文引用了 16 篇其他出版物。因为实验和模拟在完全复制生物环境方面仍然存在不足。然而,近年来在实验和计算方法方面取得的进步仍在进行中,有可能推动对实际生理环境中生物系统行为的更仔细检查。本文引用了 16 篇其他出版物。这篇文章尚未被其他出版物引用。本文引用了 16 篇其他出版物。因为实验和模拟在完全复制生物环境方面仍然存在不足。然而,近年来在实验和计算方法方面取得的进步仍在进行中,有可能推动对实际生理环境中生物系统行为的更仔细检查。本文引用了 16 篇其他出版物。这篇文章尚未被其他出版物引用。本文引用了 16 篇其他出版物。这篇文章尚未被其他出版物引用。本文引用了 16 篇其他出版物。这篇文章尚未被其他出版物引用。本文引用了 16 篇其他出版物。
更新日期:2023-05-25
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