Pseudopotentials for coarse‐grained cross‐link‐assisted modeling of protein structures

Abstract

Pseudopotentials for the chemical cross‐links comprising the glutamic‐ and aspartic‐acid side chains bridged with adipic‐ (ADH) or pimelic‐acid hydrazide (PDH), and the lysine side chains bridged with glutaric (BS2G) or suberic acid (BS3) for coarse‐grained cross‐link‐assisted simulations were determined by canonical molecular dynamics with the Amber14sb force field. The potentials depend on the distance between side‐chain ends and on side‐chain orientation, this preventing from making cross‐link contacts across the globule in simulations. The potentials were implemented in the UNRES coarse‐grained force field and their effect on the quality of models was assessed with 11 monomeric and 1 dimeric proteins, using synthetic or experimental cross‐link data. Simulations with the new potentials resulted in improvement of the generated models compared to unrestrained simulations in more instances compared to those with the statistical potentials.

Improvements and new functionalities of UNRES server for coarse-grained modeling of protein structure, dynamics, and interactions

“…Zero-length (ZL) crosslinks that occur between basic and acidic side chains or involve the N-terminal amino groups or the C-terminal carboxyl groups are also included. These restraints perform well in the data-assisted modeling of protein structure with UNRES (Leitner et al, 2014;Kogut et al, 2021).…”

“…where N d , N θ , and N γ are the numbers of terms in the expressions for the virtual-bond-length, virtual-bond-angle, and virtualbond-dihedral-angle potentials and the other symbols except for geometric variables (d Xi , θ Xi , θ Xj , and γ XiXj ) are adjustable parameters, which have been determined in (Kogut et al, 2021). The geometric variables are illustrated in Figure 2.…”

“…The example is horse heart cytochrome (PDB: 1hrc), a 105residue α-protein, which was one of the proteins used in our Frontiers in Molecular Biosciences frontiersin.org Frontiers in Molecular Biosciences frontiersin.org previous work (Kogut et al, 2021) to test the XL-MS-dataassisted functionality of the UNRES package. As opposed to that work, no secondary-structure restraints were imposed in the calculations with the UNRES server.…”

“…Recently, we developed a scale-consistent theory of coarse-grained force-field derivation ( Sieradzan et al, 2017 ; Liwo et al, 2020 ) and a new version of UNRES ( Liwo et al, 2019 ), which handles the β -strand and loop geometry much better, producing structures with a higher resolution, as demonstrated in the CASP13 ( Lubecka et al, 2019 ) and CASP14 ( Antoniak et al, 2021 ) community-wide experiments of the assessment of methods for protein-structure prediction ( https://predictioncenter.org ). The UNRES package has also been enhanced with the XL-MS ( Fajardo et al, 2019 ; Kogut et al, 2021 ) and NMR ( Lubecka and Liwo, 2021 , 2022 ) data-assisted-calculation capacities, which have recently been included in the server. Finally, the UNRES code has recently been heavily optimized for memory and speed ( Sieradzan et al, 2022b ) and the optimized code has been included in the server.…”

Recent Developments in Data-Assisted Modeling of Flexible Proteins

“…A crosslink restraint is usually imposed on the straight-line distance between the C α -atoms of the corresponding residues (Leitner et al, 2014;Merkley et al, 2014;Fajardo et al, 2019). Recently, we developed an approach in which restraints are imposed on side-chain ends and implemented it in all-atom (Gong et al, 2020) and coarse-grained (Kogut et al, 2021) molecular dynamics. This approach is more realistic because such distances are close to those between the solvent-accessible surfaces, which are targeted by the cross-linking reagents in the XL-MS experiments.…”