title: Equilibrium transitions between side-chain conformations in leucine and isoleucine.
abstract: Despite recent improvements in computational methods for protein design, we still lack a quantitative, predictive understanding of the intrinsic probabilities for amino acids to adopt particular side-chain conformations. Surprisingly, this question has remained unsettled for many years, in part because of inconsistent results from different experimental approaches. To explicitly determine the relative populations of different side-chain dihedral angles, we performed all-atom hard-sphere Langevin Dynamics simulations of leucine (Leu) and isoleucine (Ile) dipeptide mimetics with stereo-chemical constraints and repulsive-only steric interactions between non-bonded atoms. We determine the relative populations of the different χ(1) and χ(2) dihedral angle combinations as a function of the backbone dihedral angles ϕ and ψ. We also propose, and test, a mechanism for inter-conversion between the different side-chain conformations. Specifically, we discover that some of the transitions between side-chain dihedral angle combinations are very frequent, whereas others are orders of magnitude less frequent, because they require rare coordinated motions to avoid steric clashes. For example, to transition between different values of χ(2), the Leu side-chain bond angles κ(1) and κ(2) must increase, whereas to transition in χ(1), the Ile bond angles λ(1) and λ(2) must increase. These results emphasize the importance of computational approaches in stimulating further experimental studies of the conformations of side-chains in proteins. Moreover, our studies emphasize the power of simple steric models to inform our understanding of protein structure, dynamics, and design.
authors.affiliation: Department of Physics, Yale University, New Haven, Connecticut.|Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, Connecticut.
authors.forename: Diego
authors.initials: D
authors.lastname: Caballero
authors.affiliation: Department of Physics, Yale University, New Haven, Connecticut.
authors.forename: W Wendell
authors.initials: WW
authors.lastname: Smith
authors.affiliation: Department of Physics, Yale University, New Haven, Connecticut.|Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, Connecticut.|Department of Mechanical Engineering & Materials Science, Yale University, New Haven, Connecticut.|Department of Applied Physics, Yale University, New Haven, Connecticut.
authors.forename: Corey S
authors.initials: CS
authors.lastname: O'Hern
authors.affiliation: Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, Connecticut.|Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, Connecticut.|Department of Chemistry, Yale University, New Haven, Connecticut.
authors.forename: Lynne
authors.initials: L
authors.lastname: Regan
mesh_terms: D019295:Computational Biology; D057927:Hydrophobic and Hydrophilic Interactions; D007532:Isoleucine / Q000737:chemistry* / Q000378:metabolism; D007930:Leucine / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism
chemical_list: D011506:Proteins; D007532:Isoleucine; D007930:Leucine
keywords: Markov chains; NMR studies of proteins; hydrophobic amino acids; langevin dynamics of proteins; protein folding; protein structure prediction; protein-protein interactions; rotamer prediction; side-chain conformations; side-chain dihedral angles