Abstract
Dynamics of biomolecular assemblies offer invaluable insights into their functional mechanisms. For extremely large biomolecular systems, such as HIV-1 capsid that has nearly 5 millions atoms, obtaining its normal mode dynamics using even coarse-grained models can be a challenging task. In this work, we have successfully carried out a normal mode analysis of an entire HIV-1 capsid in full all-atom details. This is made possible through our newly developed BOSE (Block of Selected Elasticity) model that is founded on the principle of resonance discovered in our recent work. The resonance principle makes it possible to most efficiently compute the vibrations of a whole capsid at any given frequency by projecting the motions of component capsomeres into a narrow subspace. We have conducted also assessments of the quality of the BOSE modes by comparing them with benchmark modes obtained directly from the original Hessian matrix. Our all-atom normal mode dynamics study of the HIV-1 capsid reveals the dynamic role of the pentamers in stabilizing the capsid structure and is in agreement with experimental findings that suggest capsid disassembly and uncoating start when the pentamers become destabilized. Our results on the dynamics of hexamer pores suggest that nucleotide transport should take place mostly at hexamers near pentamers, especially at the larger hemispherical end.
Highlights
The recent breakthroughs in experimental technology for structure determination, especially in single-particle cryo-electron microscopy [2], have helped unveil many large structure assemblies at near atomic resolution for the first time
Supramolecular assemblies are large biomolecular complexes composed of hundreds or even thousands of protein chains. They function as molecular machines or as large containers that store or facilitate the chemical reactions of other molecules. Their functional mechanisms are tightly linked to their structures and intrinsic dynamics
Due to breakthroughs in experimental techniques, many supramolecular assemblies have been determined, such as the capsid of human immunodeficiency virus (HIV) that is composed of nearly 5 millions of atoms
Summary
The recent breakthroughs in experimental technology for structure determination, especially in single-particle cryo-electron microscopy [2], have helped unveil many large structure assemblies at near atomic resolution for the first time. The source of the challenge in running NMA is the size of the Hessian matrix, whose dimension is in the same order as the number of atoms in the system. Similar to standard eigenvalue solvers, this type of approaches still require knowledge of a full Hessian matrix (in the sparse matrix format), which can become severely limiting when dealing with extremely large systems such as HIV-1 capsid that has nearly 5 million atoms. The advantage of this type of approaches is that the accuracy is fully maintained and not compromised in any way
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