Multiscale Modeling of Proteins

摘要

Tnhe activity within a living cell is based on a complex net-nwork of interactions among biomolecules, exchanging infor-nmation and energy through biochemical processes. These eventsnoccur on different scales, from the nano- to the macroscale, span-nning about 10 orders of magnitude in the space domain and 15norders of magnitude in the time domain. Consequently, many dif-nferent modeling techniques, each proper for a particular time ornspace scale, are commonly used. In addition, a single processnoften spans more than a single time or space scale. Thus, thennecessity arises for combining the modeling techniques in mul-ntiscale approaches.nIn this Account, I first review the different modeling meth-nods for bio-systems, from quantum mechanics to the coarse-ngrained and continuum-like descriptions, passing through thenatomistic force field simulations. Special attention is devoted to their combination in different possible multiscale approachesnand to the questions and problems related to their coherent matching in the space and time domains. These aspects arenoften considered secondary, but in fact, they have primary relevance when the aim is the coherent and complete descrip-ntion of bioprocesses.nSubsequently, applications are illustrated by means of two paradigmatic examples: (i) the green fluorescent protein (GFP)nfamily and (ii) the proteins involved in the human immunodeficency virus (HIV) replication cycle. The GFPs are currently onenof the most frequently used markers for monitoring protein trafficking within living cells; nanobiotechnology and cell biol-nogy strongly rely on their use in fluorescence microscopy techniques. A detailed knowledge of the actions of the virus-nspecific enzymes of HIV (specifically HIV protease and integrase) is necessary to study novel therapeutic strategies againstnthis disease. Thus, the insight accumulated over years of intense study is an excellent framework for this Account.nThe foremost relevance of these two biomolecular systems was recently confirmed by the assignment of two of the Nobelnprizes in 2008: in chemistry for the discovery of GFP and in medicine for the discovery of HIV. Accordingly, these proteinsnwere studied with essentially all of the available modeling techniques, making them ideal examples for studying the detailsnof multiscale approaches in protein modeling.