Mechanical and Assembly Units of Viral Capsids Identified via Quasi-Rigid Domain Decomposition

et al. (2013) Mechanical and Assembly Units of Viral Capsids Identified via Quasi-Rigid Domain Decomposition. PLoS Comput Biol 9(11): e1003331. doi:10.1371/journal.pcbi.1003331 Mechanical and Assembly Units of Viral Capsids Identified via Quasi-Rigid Domain Decomposition Guido Polles 0 Giuliana Indelicato 0 Raffaello Potestio 0 Paolo Cermelli 0 Reidun Twarock 0 Cristian Micheletti 0 Avner Schlessinger, Icahn School of Medicine at Mount Sinai, United States of America 0 1 International School for Advanced Studies (SISSA) , Trieste , Italy , 2 York Centre for Complex Systems Analysis, Department of Mathematics, University of York, York, United Kingdom, 3 Max-Planck-Institut f u r Polymerforschung , Mainz, Germany, 4 Dipartimento di Matematica , Universita` di Torino , Torino , Italy Key steps in a viral life-cycle, such as self-assembly of a protective protein container or in some cases also subsequent maturation events, are governed by the interplay of physico-chemical mechanisms involving various spatial and temporal scales. These salient aspects of a viral life cycle are hence well described and rationalised from a mesoscopic perspective. Accordingly, various experimental and computational efforts have been directed towards identifying the fundamental building blocks that are instrumental for the mechanical response, or constitute the assembly units, of a few specific viral shells. Motivated by these earlier studies we introduce and apply a general and efficient computational scheme for identifying the stable domains of a given viral capsid. The method is based on elastic network models and quasi-rigid domain decomposition. It is first applied to a heterogeneous set of well-characterized viruses (CCMV, MS2, STNV, STMV) for which the known mechanical or assembly domains are correctly identified. The validated method is next applied to other viral particles such as L-A, Pariacoto and polyoma viruses, whose fundamental functional domains are still unknown or debated and for which we formulate verifiable predictions. The numerical code implementing the domain decomposition strategy is made freely available. - The genomic material of many viruses is encapsidated inside icosahedral protein shells with diameters in the 20100 nm range. The number of structurally inequivalent protein units that tessellate these capsids is usually very small [1,2]. This, in turn, is reflected in the limited repertoire of viable capsid shapes with icosahedral symmetry [3]. Understanding the organization of viral capsids at levels that are intermediate between the single protein units and the fully assembled, infectious particles is crucial to elucidate key aspects of the viral life cycle. These include the molecular basis of capsid conformational changes, such as swelling or maturation events [4], as well as the assemby/disassembly of virion particles [58]. Both these processes, in fact, are best characterised and rationalised in terms of the typically multimeric protein units [9] that behave as approximately rigid units in the capsids conformational mechanics or act as basic assembly/disassembly units. The identification of these units has so far been carried out for few viruses using advanced experimental or numerical techniques for probing and modelling capsids assembly/disassembly kinetics and thermodynamics, internal dynamics and response to mechanical stress [1021]. These approaches have proved extremely valuable to gain insight into various mechanisms controlling the physico-chemical behaviour of few specific viruses [1012,1416,2224]. For instance, nano-indentation experiments, where viral particles are subject to mechanical stress and fatigue by atomic force microscopy, have singled out the mechanical building blocks of viral capsids and elucidated the mechanisms of genome uncoating [25]. However, the systematic application of these techniques has been hindered either by the difficulty of transferring the methodologies across different virus types or by their severe experimental/computational demands. As a step towards developing a general scheme for identifying functional and structural units in viral shells, here we introduce and apply a novel and efficient computational strategy that can single out capsid domains that, according to various criteria, are expected to be mechanically stable. The method consists of a decomposition of the capsid into quasi-rigid units based on a suitable analysis of its internal dynamics. In accord with the mesoscopic spirit of the approach, the sought internal dynamics can be efficiently obtained from elastic network approaches, in place of computationally-demanding molecular dynamics simulations. The variational decomposition strategy is applied to several viruses covering a wide range of sizes and capsid classes, from T = 1 to pT = 7. For validation purposes, the set includes several well-characterised instances: the cowpea chlorotic mottle virus (CCMV), the MS2 virus, the satellite tobacco necrosis virus The genetic material of viruses is packaged inside capsids constituted from a few tens to thousands of proteins. The latter can organize in multimers that serve as fundamental blocks for the viral shell assembly or that control the capsid conformational transitions and response to mechanical stress. In this work, we introduce and apply a computational scheme that identifies the fundamental protein blocks from the structural fluctuations of the capsids in thermal equilibrium. These can be derived from phenomenological elastic network models with minimal computational expenditure. Accordingly, the basic functional protein units of a capsid can be obtained from the sole input of the capsid crystal structure. The method is applied to a heterogeneous set of viruses of various size and geometries. These include well-characterised instances for validation purposes, as well as debated ones for which predictions are formulated. (SNTV) and satellite tobacco mosaic virus (STMV). The units obtained from the decomposition are in excellent agreement with known basic blocks of the assembly/disassembly process or of the structural transitions. These successful comparisons give confidence in the viability of the strategy for identifying putative functional units of viral capsids. This suggests that the method could be profitably used for interpreting viral assembly, disassembly and genome uncoating experiments or as a predictive tool. Towards this latter goal, we conclude the present study by formulating predictions for a number of viruses whose capsid structure is available but whose functional units are still unknown, or debated. This prediction set includes the L-A (pT = 2), Pariacoto (T = 3) and polyoma viruses (pT = 7). The decomposition algorithm, which is formulated in a general and hence transferable way, is made freely available for academic use at the link: http://people.sissa.it/,michelet/vircapdomains. The main objective of this study is to inv (...truncated)