Molecular dynamics simulations of macromolecular crystals

Cerutti, David S.; Case, David A.

doi:10.1002/wcms.1402

Cited by 29 publications

(22 citation statements)

References 144 publications

(175 reference statements)

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“…All-atom molecular dynamics simulations. Although all-atom MD simulations have previously been used to investigate the contribution of protein dynamics to diffuse scattering 12,16,29,[32][33][34] , the effect of long-ranged correlations due to lattice disorder has not been examined. We thus performed all-atom MD simulations of triclinic lysozyme crystals as a function of supercell size (Methods).…”

Section: Resultsmentioning

confidence: 99%

Diffuse X-ray scattering from correlated motions in a protein crystal

2020

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Protein dynamics are integral to biological function, yet few techniques are sensitive to collective atomic motions. A long-standing goal of X-ray crystallography has been to combine structural information from Bragg diffraction with dynamic information contained in the diffuse scattering background. However, the origin of macromolecular diffuse scattering has been poorly understood, limiting its applicability. We present a finely sampled diffuse scattering map from triclinic lysozyme with unprecedented accuracy and detail, clearly resolving both the inter-and intramolecular correlations. These correlations are studied theoretically using both all-atom molecular dynamics and simple vibrational models. Although lattice dynamics reproduce most of the diffuse pattern, protein internal dynamics, which include hinge-bending motions, are needed to explain the short-ranged correlations revealed by Patterson analysis. These insights lay the groundwork for animating crystal structures with biochemically relevant motions.

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Section: Resultsmentioning

confidence: 99%

Diffuse X-ray scattering from correlated motions in a protein crystal

2020

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“…All-atom molecular dynamics simulations. Although all-atom MD simulations have previously been used to investigate the contribution of protein dynamics to diffuse scattering (12,16,29,(32)(33)(34), the effect of long-ranged correlations due to lattice disorder has not been examined. We thus performed all-atom MD simulations of triclinic lysozyme crystals as a function of supercell size (Supplementary Methods).…”

Section: Resultsmentioning

confidence: 99%

Diffuse X-ray Scattering from Correlated Motions in a Protein Crystal

Meisburger

Case

Ando

2019

Preprint

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Protein dynamics are integral to biological function, yet few techniques are sensitive to collective atomic motions. A long-standing goal of X-ray crystallography has been to combine structural information from Bragg diffraction with dynamic information contained in the diffuse scattering background. However, the origin of macromolecular diffuse scattering has been poorly understood, limiting its applicability. We present a detailed diffuse scattering map from triclinic lysozyme that resolves both inter-and intramolecular correlations. These correlations are studied theoretically using both all-atom molecular dynamics and simple vibrational models. Although lattice dynamics reproduce most of the diffuse pattern, protein internal dynamics, which include hinge-bending motions, are needed to explain the short-ranged correlations revealed by Patterson analysis. These insights lay the groundwork for animating crystal structures with biochemically relevant motions.

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“…Allowing select amino acids known to be more conformationally labile (such as the short region linking the short and long components of the class I MHC α2 helix) may lead to further improvements. We might also consider the influence of crystalline environments at cryogenic temperatures, which may limit overall accuracy with energy functions that incorporate other data ( 78 ).…”

Section: Discussionmentioning

confidence: 99%

Physicochemical Heuristics for Identifying High Fidelity, Near-Native Structural Models of Peptide/MHC Complexes

2022

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There is long-standing interest in accurately modeling the structural features of peptides bound and presented by class I MHC proteins. This interest has grown with the advent of rapid genome sequencing and the prospect of personalized, peptide-based cancer vaccines, as well as the development of molecular and cellular therapeutics based on T cell receptor recognition of peptide-MHC. However, while the speed and accessibility of peptide-MHC modeling has improved substantially over the years, improvements in accuracy have been modest. Accuracy is crucial in peptide-MHC modeling, as T cell receptors are highly sensitive to peptide conformation and capturing fine details is therefore necessary for useful models. Studying nonameric peptides presented by the common class I MHC protein HLA-A*02:01, here we addressed a key question common to modern modeling efforts: from a set of models (or decoys) generated through conformational sampling, which is best? We found that the common strategy of decoy selection by lowest energy can lead to substantial errors in predicted structures. We therefore adopted a data-driven approach and trained functions capable of predicting near native decoys with exceptionally high accuracy. Although our implementation is limited to nonamer/HLA-A*02:01 complexes, our results serve as an important proof of concept from which improvements can be made and, given the significance of HLA-A*02:01 and its preference for nonameric peptides, should have immediate utility in select immunotherapeutic and other efforts for which structural information would be advantageous.

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Molecular dynamics simulations of macromolecular crystals

Cited by 29 publications

References 144 publications

Diffuse X-ray scattering from correlated motions in a protein crystal

Diffuse X-ray scattering from correlated motions in a protein crystal

Diffuse X-ray Scattering from Correlated Motions in a Protein Crystal

Physicochemical Heuristics for Identifying High Fidelity, Near-Native Structural Models of Peptide/MHC Complexes

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