NEST CNR-INFM, and Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56126 Pisa, Italy.
Acc Chem Res. 2010 Feb 16;43(2):220-30. doi: 10.1021/ar9001476.
The activity within a living cell is based on a complex network of interactions among biomolecules, exchanging information and energy through biochemical processes. These events occur on different scales, from the nano- to the macroscale, spanning about 10 orders of magnitude in the space domain and 15 orders of magnitude in the time domain. Consequently, many different modeling techniques, each proper for a particular time or space scale, are commonly used. In addition, a single process often spans more than a single time or space scale. Thus, the necessity arises for combining the modeling techniques in multiscale approaches. In this Account, I first review the different modeling methods for bio-systems, from quantum mechanics to the coarse-grained and continuum-like descriptions, passing through the atomistic force field simulations. Special attention is devoted to their combination in different possible multiscale approaches and to the questions and problems related to their coherent matching in the space and time domains. These aspects are often considered secondary, but in fact, they have primary relevance when the aim is the coherent and complete description of bioprocesses. Subsequently, applications are illustrated by means of two paradigmatic examples: (i) the green fluorescent protein (GFP) family and (ii) the proteins involved in the human immunodeficiency virus (HIV) replication cycle. The GFPs are currently one of the most frequently used markers for monitoring protein trafficking within living cells; nanobiotechnology and cell biology strongly rely on their use in fluorescence microscopy techniques. A detailed knowledge of the actions of the virus-specific enzymes of HIV (specifically HIV protease and integrase) is necessary to study novel therapeutic strategies against this disease. Thus, the insight accumulated over years of intense study is an excellent framework for this Account. The foremost relevance of these two biomolecular systems was recently confirmed by the assignment of two of the Nobel prizes in 2008: in chemistry for the discovery of GFP and in medicine for the discovery of HIV. Accordingly, these proteins were studied with essentially all of the available modeling techniques, making them ideal examples for studying the details of multiscale approaches in protein modeling.
活细胞中的活动是基于生物分子之间复杂的相互作用网络，通过生化过程交换信息和能量。这些事件发生在不同的尺度上，从纳米到宏观，跨越了大约 10 个数量级的空间域和 15 个数量级的时间域。因此，通常使用许多不同的建模技术，每种技术都适用于特定的时间或空间尺度。此外，单个过程通常跨越多个时间或空间尺度。因此，需要将建模技术组合到多尺度方法中。在本说明中，我首先回顾了生物系统的不同建模方法，从量子力学到粗粒化和连续体描述，再到原子力场模拟。特别关注它们在不同多尺度方法中的组合，以及在空间和时间域中相关的一致性匹配问题和问题。这些方面通常被认为是次要的，但实际上，当目标是对生物过程进行连贯和完整的描述时，它们具有主要的相关性。随后，通过两个范例应用来说明这些方面：（i）绿色荧光蛋白（GFP）家族和（ii）人类免疫缺陷病毒（HIV）复制周期中涉及的蛋白质。GFP 目前是监测活细胞内蛋白质运输的最常用标记物之一；纳米生物技术和细胞生物学强烈依赖于它们在荧光显微镜技术中的应用。了解 HIV 病毒特异性酶（特别是 HIV 蛋白酶和整合酶）的作用对于研究针对这种疾病的新治疗策略是必要的。因此，多年来积累的深入研究的见解是本说明的极好框架。这两个生物分子系统的最重要相关性最近在 2008 年诺贝尔化学奖和诺贝尔医学奖的授予中得到了证实：诺贝尔化学奖授予 GFP 的发现，诺贝尔医学奖授予 HIV 的发现。因此，这些蛋白质基本上使用了所有可用的建模技术进行了研究，使它们成为研究蛋白质建模中多尺度方法细节的理想范例。
