Non-bonded force field model with advanced restrained electrostatic potential charges (RESP2)

The restrained electrostatic potential (RESP) approach is a highly regarded and widely used method of assigning partial charges to molecules for simulations. RESP uses a quantum-mechanical method that yields fortuitous overpolarization and thereby accounts only approximately for self-polarization of molecules in the condensed phase. Here we present RESP2, a next generation of this approach, where the polarity of the charges is tuned by a parameter, δ, which scales the contributions from gas- and aqueous-phase calculations. When the complete non-bonded force field model, including Lennard-Jones parameters, is optimized to liquid properties, improved accuracy is achieved, even with this reduced set of five Lennard-Jones types. We argue that RESP2 with δ  ≈ 0.6 (60% aqueous, 40% gas-phase charges) is an accurate and robust method of generating partial charges, and that a small set of Lennard-Jones types is a good starting point for a systematic re-optimization of this important non-bonded term. The restrained electrostatic potential (RESP) is a widely used method for assigning partial charges to organic molecules for molecular dynamics simulations, but it imperfectly accounts for self-polarization in solution. Here, RESP is updated by co-optimizing the polarity of the charges it generates, along with atomic Lennard-Jones parameters, to yield an improved model of non-bonded interactions.