The Power of Hard-Sphere Models: Explaining Side-Chain Dihedral Angle Distributions of Thr and Val

Zhou, Alice; O’Hern, Corey S.; Regan, Lynne

doi:10.1016/j.bpj.2012.01.061

Cited by 30 publications

(34 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Instead, we seek to describe the exact stereochemistry of a dipeptide mimetic. The results we present, along with our prior studies of the side‐chain dihedral angle distributions of different amino acids (AZ, CO, LR, submitted), make it clear that steric repulsion is the dominant force in specifying the allowed backbone and side‐chain conformations of a large set of amino acids. We believe that with Amber and CHARMM, the contribution of steric repulsion is being outweighed by the contributions from other terms in the force field.…”

Section: Resultssupporting

confidence: 54%

Intrinsic α‐helical and β‐sheet conformational preferences: A computational case study of alanine

et al. 2014

Self Cite

View full text Add to dashboard Cite

A fundamental question in protein science is what is the intrinsic propensity for an amino acid to be in an a-helix, b-sheet, or other backbone dihedral angle (/-w) conformation. This question has been hotly debated for many years because including all protein crystal structures from the protein database, increases the probabilities for a-helical structures, while experiments on small peptides observe that b-sheet-like conformations predominate. We perform molecular dynamics (MD) simulations of a hard-sphere model for Ala dipeptide mimetics that includes steric interactions between nonbonded atoms and bond length and angle constraints with the goal of evaluating the role of steric interactions in determining protein backbone conformational preferences. We find four key results. For the hard-sphere MD simulations, we show that (1) b-sheet structures are roughly three and half times more probable than a-helical structures, (2) transitions between a-helix and b-sheet structures only occur when the backbone bond angle s (NAC a AC) is greater than 110 , and (3) the probability distribution of s for Ala conformations in the "bridge" region of /-w space is shifted to larger angles compared to other regions. In contrast, (4) the distributions obtained from Amber and CHARMM MD simulations in the bridge regions are broader and have increased s compared to those for hard sphere simulations and from high-resolution protein crystal structures. Our results emphasize the importance of hard-sphere interactions and local stereochemical constraints that yield strong correlations between /-w conformations and s.

show abstract

Section: Resultssupporting

confidence: 54%

Intrinsic α‐helical and β‐sheet conformational preferences: A computational case study of alanine

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…10, we show that the Ramachandran plot for the random walk all-atom model of α-synuclein with no attractive hydrophobic and electrostatic interactions and atom sizes from Ref. [14] closely resembles that for dipeptides with a highly populated α-helix and β-sheet regions, even without modeling backbone hydrogen bonding interactions. In Fig.…”

Section: Appendix A: Calibration Of Atom Sizesmentioning

confidence: 68%

“…We used the atom sizes (for hydrogen, carbon, oxygen, nitrogen, and sulfur) from Ref. [14] after verifying that the backbone dihedral angles for the allatom model sample the sterically allowed φ and ψ values in the Ramachandran map [15] when V = V bl + V ba + V da + V r TABLE I. Hydrophobicity indices h i that range from 0 (hydrophilic) to 1 (hydrophobic) for residues in α-synuclein at pH 7.4 [16]. The hydrophobic interactions between residues were modeled using the attractive Lennard-Jones potential…”

Section: A All-atom Modelmentioning

confidence: 99%

Molecular simulations of the fluctuating conformational dynamics of intrinsically disordered proteins

et al. 2012

View full text Add to dashboard Cite

Intrinsically disordered proteins (IDPs) do not possess well-defined three-dimensional structures in solution under physiological conditions. We develop all-atom, united-atom, and coarse-grained Langevin dynamics simulations for the IDP α-synuclein that include geometric, attractive hydrophobic, and screened electrostatic interactions and are calibrated to the inter-residue separations measured in recent single-molecule fluorescence energy transfer (smFRET) experiments. We find that α-synuclein is disordered, with conformational statistics that are intermediate between random walk and collapsed globule behavior. An advantage of calibrated molecular simulations over constraint methods is that physical forces act on all residues, not only on residue pairs that are monitored experimentally, and these simulations can be used to study oligomerization and aggregation of multiple α-synuclein proteins that may precede amyloid formation.

show abstract

“…The atomic diameters σ i , C(sp 3 ): 1.5 Å, C(sp 2 ): 1.4 Å, N: 1.4 Å, O: 1.35 Å, and H: 1.05 Å, are similar to values employed in previous studies, except the oxygen diameter was decreased from 1.4 Å to 1.35 Å to improve sampling in ϕ‐ψ space . Hydrogen atoms were added to the dipeptide using the REDUCE software program .…”

Section: Methodsmentioning

confidence: 74%

Equilibrium transitions between side-chain conformations in leucine and isoleucine

et al. 2015

Self Cite

View full text Add to dashboard Cite

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.

show abstract

The Power of Hard-Sphere Models: Explaining Side-Chain Dihedral Angle Distributions of Thr and Val

Cited by 30 publications

References 42 publications

Intrinsic α‐helical and β‐sheet conformational preferences: A computational case study of alanine

Intrinsic α‐helical and β‐sheet conformational preferences: A computational case study of alanine

Molecular simulations of the fluctuating conformational dynamics of intrinsically disordered proteins

Equilibrium transitions between side-chain conformations in leucine and isoleucine

Contact Info

Product

Resources

About