Cabezón Alfonso, Garcia-Fandino Rebeca, Piñeiro Ángel
Department of Organic Chemistry, Center for Research in Biological Chemistry and Molecular Materials, University of Santiago de Compostela, CIQUS, E-15782 Santiago de Compostela, Spain.
Department of Applied Physics, Faculty of Physics, University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain.
J Chem Theory Comput. 2025 Jun 10;21(11):5724-5735. doi: 10.1021/acs.jctc.5c00126. Epub 2025 May 28.
Self-assembled nanotubes (SCPNs) formed by alternating chirality α-Cyclic Peptides (d,l-α-CPs) have presented interesting biological applications, such as antimicrobial activity or ion transmembrane transport. Due to difficulties to follow these processes with experimental techniques, Molecular Dynamics (MD) simulations have been commonly used to understand the mechanism that led to their biological activity. However, the high computational cost of atomic resolution simulations makes them unsuitable for simulating dynamic processes involving multiple units like their self-assembly in different environments. In this regard, coarse-grain (CG) models might represent a more feasible option. However, general coarse-grained force fields such as MARTINI do not explicitly account for noncovalent interactions, such as hydrogen bonding, which are essential for secondary structure formation and the self-assembly of proteins and peptides. This problem becomes particularly important when simulating CPs due to the specific directionality of their interactions. In a previous work, it has been proven how MARTINI classical parametrization overestimated the self-assembly of CPs not distinguishing parallel and antiparallel interactions as well as allowing forbidden rotational angles. The so-called MA(R/S)TINI force field fixed the problem by including two extra particles into the backbone bead while preserving the behavior of several CP sequences in the presence of different membrane models. However, this new parametrization presented a much higher CP-CP interaction energy, being another critical issue for self-assembly overestimation. The release of MARTINI 3 expanded the scope of the force field by introducing new particles and labels specifically tailored to improve the representation of noncovalent interactions. Nevertheless, since it uses the same mapping strategy for protein backbones, this new version also failed at capturing the specific directionality of CPs. Taking advantage of the new possibilities offered by MARTINI 3, MA(R/S)TINI has been updated in the present work. This new version uses a new mapping of CPs based on original beads of the force field and releases the restraints previously imposed on the lateral side chains of the CPs. This new parameterization fixes the formerly overestimated interaction energy between CPs in both parallel and antiparallel orientations, while preserving the advantages of the previous version of MA(R/S)TINI. The new parametrization provided in the present work is aimed to facilitate the understanding, design, and optimization of new bioactive CPs based on CG-MD simulations.
由手性交替的α-环肽（d，l-α-CPs）形成的自组装纳米管（SCPNs）展现出了有趣的生物学应用，比如抗菌活性或离子跨膜运输。由于用实验技术追踪这些过程存在困难，分子动力学（MD）模拟常被用于理解导致其生物学活性的机制。然而，原子分辨率模拟的高计算成本使其不适用于模拟涉及多个单元的动态过程，如它们在不同环境中的自组装。在这方面，粗粒度（CG）模型可能是一个更可行的选择。然而，像MARTINI这样的通用粗粒度力场没有明确考虑非共价相互作用，如氢键，而氢键对于蛋白质和肽的二级结构形成及自组装至关重要。由于CPs相互作用的特定方向性，在模拟CPs时这个问题变得尤为重要。在之前的一项工作中，已经证明了MARTINI经典参数化如何高估了CPs的自组装，没有区分平行和反平行相互作用以及允许了禁止的旋转角度。所谓的MA(R/S)TINI力场通过在主链珠子中加入两个额外粒子解决了这个问题，同时在不同膜模型存在的情况下保留了几个CP序列的行为。然而，这种新的参数化呈现出高得多的CP-CP相互作用能，这是自组装高估的另一个关键问题。MARTINI 3的发布通过引入专门为改善非共价相互作用表示而定制的新粒子和标签扩展了力场的范围。然而，由于它对蛋白质主链使用相同的映射策略，这个新版本在捕捉CPs的特定方向性方面也失败了。利用MARTINI 3提供的新可能性，MA(R/S)TINI在本工作中得到了更新。这个新版本基于力场的原始珠子对CPs进行了新的映射，并释放了先前对CPs侧链施加的限制。这种新的参数化修正了之前在平行和反平行取向中CPs之间高估的相互作用能，同时保留了MA(R/S)TINI先前版本的优点。本工作中提供的新参数化旨在促进基于CG-MD模拟对新型生物活性CPs的理解、设计和优化。
