Understanding the native fluctuations of protein cores

Understanding how thermal fluctuations affect protein structure is essential for characterizing the energy landscape of proteins, as well as determining the response to amino acid mutations. Protein structures obtained from liquid-state NMR, unlike those from x-ray crystallography, provide a number of model structures that satisfy the experimental constraints. Using a database of high-quality, paired NMR and x-ray crystal structures, we have shown that there are important differences between NMR structures and those solved by x-ray crystallography including differences in the root-mean-square deviations of the core C_α atomic positions, identities of the core amino acids, and packing fractions of core residues. In this work, we carry out all-atom molecular dynamics simulations to study the fluctuating conformational dynamics of wildtype globular proteins, as well as mutants, in aqueous solvent at room temperature. We study the fluctuating conformations using several metrics including the radius of gyration R_g, packing fraction, and C_α atomic positions. We find that most often the MD simulations sample conformations that are representative of the NMR and x-ray conformations, but ~40% of the sampled structures are not consistent with the experimental structures, with larger R_g and lower packing fractions.