Abstract
Molecular mechanics force field parameters for macromolecules, such as proteins, are traditionally fit to reproduce experimental properties of small molecules, and thus, they neglect system-specific polarization. In this paper, we introduce a complete protein force field that is designed to be compatible with the quantum mechanical bespoke (QUBE) force field by deriving nonbonded parameters directly from the electron density of the specific protein under study. The main backbone and sidechain protein torsional parameters are rederived in this work by fitting to quantum mechanical dihedral scans for compatibility with QUBE nonbonded parameters. Software is provided for the preparation of QUBE input files. The accuracy of the new force field, and the derived torsional parameters, is tested by comparing the conformational preferences of a range of peptides and proteins with experimental measurements. Accurate backbone and sidechain conformations are obtained in molecular dynamics simulations of dipeptides, with NMR J coupling errors comparable to the widely used OPLS force field. In simulations of five folded proteins, the secondary structure is generally retained, and the NMR J coupling errors are similar to standard transferable force fields, although some loss of the experimental structure is observed in certain regions of the proteins. With several avenues for further development, the use of system-specific nonbonded force field parameters is a promising approach for next-generation simulations of biological molecules.
Highlights
Molecular mechanics (MM) force fields for biomolecular simulations have been under continuous development for many years.[1−5] In traditional transferable force fields, every atom in a molecule is assigned a type based on its atomic number, bonding, and local chemical environment
For the alanine and glycine scans, the error for the quantum mechanical bespoke (QUBE) force field evaluated using eq 5 is 1.25 kcal/mol compared to 0.93 kcal/mol for OPLS-AA/M, which is a reasonable level of agreement
For the sidechain torsional parameters (Section S3.3), the mean error in the recreation of the quantum mechanical (QM) potential energy scans for the QUBE force field is 1.29 kcal/mol compared to 1.12 kcal/mol for OPLS-AA/M
Summary
Molecular mechanics (MM) force fields for biomolecular simulations have been under continuous development for many years.[1−5] In traditional transferable force fields, every atom in a molecule is assigned a type based on its atomic number, bonding, and local chemical environment. It is acknowledged that transferable force fields are not sufficiently accurate.[8] When building force fields for small molecules, the atomic charges are usually assigned in a system-specific or “bespoke” manner, using methods such as RESP, CM1, or AM1-BCC.[9−13] This is because it is well-known that atomic charges polarize in response to their chemical environment (for example, the presence of electrondonating or electron-withdrawing groups).[8] Bespoke charges are usually assumed to be compatible with the fixed Lennard-Jones parameters of the force field, these have been shown to be dependent on the local environment of the atom.[14] proteins must experience polarization effects in both the charges and Lennard-Jones parameters, protein force field parameters have always, to date, been assigned from a transferable library.[1−3,15] This leads to an inconsistency in the parametrization strategy used for protein force fields and bespoke small-molecule force fields. This is potentially problematic when studying properties that depend on the electrostatic potentials of proteins, such as their interactions with small molecules, and there is no clear way around this using traditional force field fitting methods
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
