Integrative Structural Modeling Of Large Biomolecules:Methods Development And Applications

Structures and dynamics of biomolecules are closely related to their functions,such as DNA replication,cell differentiation and many other important biological processes.Structural biologists determine three dimensional(3D)structures of biomolecules to better understand their functions,which is sometimes challenging.Crystallography,nuclear magnetic resonance(NMR)and cryo-electron microscopy(cryo-EM)are the most widely used high-resolution techniques in structure determination of biomolecules.Other complementary techniques,such as SAXS and most EM can obtain low resolution structural information.For some biomolecules or their assemblies,any single one of these techniques might encounter limitations in determining their structures,The notion "integrative structural biology" has recently been proposed,where we can adopt computer simulations to construct the structural models of biomolecules integrating various resolution structural data.The modeling procedure that combines known high resolution structural information and low resolution structural information is called "integrative structural modeling".The main concept in "integrative structural modeling" is scoring function,conformational sampling and cross-validation.Much progress and improvement have been accomplished in modeling macromolecular structure and dynamics.However,due to the complexity of biomolecules,fast and effectively sampling is still a challenge and is often one of the main challenges in "integrative structural modeling".The most important algorithm of conformational sampling is atomistic molecular dynamics simulations,which is also known as conventional molecular dynamics(MD)simultaions.Due to the many degrees of freedom of a biomolecule,it is very difficult to sample the conformational space efficiently by conventional MD simulations.Thus,we may turn to enhanced sampling or coarse grained MD simulations to sample the conformational space more effectively.In some cases,multi-scale MD simulations are needed to explore the conformational spaces of biomolecules as well as to study the detailed atomistc mechanisms of structural and functional relationships of biomolecules.Under the framework of "integrative structural modeling",we have proposed the following computational tools:a principle component analysis(PCA)based enhanced sampling MD simulation technique,a Bayes based reverse mapping tool that reverse mapping multi-scale coarse grained(CG)structural models to atomistic structural models and a general purpose structural modeling tool that based on parallel cascade selection MD simulations.Meanwhile,we carried out multi-scale MD simulations to study the conformational dynamics of nucleosome core particles containing histone variant H2A.B integrating SAXS and other experimental data.