Computational prediction of native protein-protein interfaces still remains a challenging task. In virus capsids, each protein unit is in contact with copies of itself through several interfaces. The relative strengths of the different contacts affect the dynamics of the assembly, especially if the process is hierarchical. We investigate the dimerization of the salt-stable cowpea chlorotic mottle virus (CCMV) capsid protein using a combination of different computational tools. The best predictions of dimer configurations provided by blind docking with ZDOCK are rescored using geometry optimization with the Amber and Rosetta force fields. We also evaluate the relative stabilities of the three main interfaces present in the icosahedral capsid using locally restricted docking with Rosetta. Both the rescoring and locally restricted docking results report a particularly stable protein-protein interface, which is the most likely intermediate during the first stage of the hierarchical capsid assembly. The blind docking results rescored with both Amber and Rosetta yield docking funnels, i.e., three or more near-native structures among the top five predictions. The results support experimental observations on in vitro assembly of CCMV capsids. The cross-validation of the results suggests that energy-landscape-based methods with biomolecular force fields have the potential to improve existing docking procedures.
Intermediates of the self-assembly process of the salt stable cowpea chlorotic mottle virus (ss-CCMV) capsid can be modelled atomistically on realistic computational timescales either by studying oligomers in equilibrium or by focusing on their dissociation instead of their association. Our previous studies showed that among the three possible dimer interfaces in the icosahedral capsid, two are thermodynamically relevant for capsid formation. The aim of the current study is to evaluate the relative structural stabilities of the three different ss-CCMV dimers and to find and understand the conditions that lead to their dissociation. Long timescale molecular dynamics simulations at 300 K of the various dimers and of the pentamer of dimers underscore the importance of large contact surfaces on stabilizing the capsid subunits within an oligomer. Simulations in implicit solvent show that at higher temperature (350 K), the N-terminal tails of the protein units act as tethers, delaying dissociation for all but the most stable interface. The pentamer of dimers is also found to be stable on long timescales at 300 K, with an inherent flexibility of the outer protein chains.
Parts of the self-assembly process of the salt stable cowpea chlorotic mottle virus (ss-CCMV) capsid can be modelled atomistically on realistic computational timescales only if we focus on the dissociation of protein complexes instead of their aggregation. The aim of the current study is to find and understand the conditions that lead to the separation of ss-CCMV capsid protein dimers. Our previous studies showed that among the three possible interfaces in the icosahedral capsid, two (T1 and T2) are important during capsid formation. Long timescale molecular dynamics simulations of the various dimers and the pentamer of dimers underscore the importance of large contact surfaces on stabilizing the capsid subunits within an oligomer. At higher temperature, the N-terminal tails of the protein units act as tethers, delaying dissociation for all but the most stable (T1) interfaces, therefore their flexibility likely has an important role during the self-assembling process, as tethering increases the effective concentration of the monomers and the likelihood of finding native contacts. The pentamer of dimers is also found to be stable on long timescales, with an inherent flexibility of the outer protein chains.
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