Pseudobond parameters for QM/MM studies involving nucleosides, nucleotides, and their analogs

Abstract

In biological systems involving nucleosides, nucleotides, or their respective analogs, the ribose sugar moiety is the most common reaction site, for example, during DNA replication and repair. However, nucleic bases, which comprise a sizable portion of nucleotide molecules, are usually unreactive during such processes. In quantum mechanical/molecular simulations of nucleic acid reactivity, it may therefore be advantageous to describe specific ribosyl or ribosyl phosphate groups quantum mechanically and their respective nucleic bases with a molecular mechanics potential function. Here, we have extended the pseudobond approach to enable quantum mechanical/molecular mechanical simulations involving nucleotides, nucleosides, and their analogs in which the interface between the two subsystems is located between the sugar and the base, namely, the C(sp 3 )-N(sp 2 ) bond. The pseudobond parameters were optimized on a training set of 10 molecules representing several nucleotide and nucleoside bases and analogs, and they were then tested on a larger test set of 20 diverse molecules. Particular emphasis was placed on providing accurate geometries and electrostatic properties, including electrostatic potential, natural bond orbital (NBO) and atoms in molecules (AIM) charges and AIM first moments. We also tested the optimized parameters on five nucleotide and nucleoside analogues of pharmaceutical relevance and a small polypeptide (triglycine). Accuracy was maintained for these systems, which highlights the generality and transferability of the pseudobond approach.

Towards large scale hybrid QM/MM dynamics of complex systems with advanced point dipole polarizable embeddings

“…In this work we apply the recently proposed PBs by Yang and co-workers. 22,43 The use of PBs for QM/AMOEBA hybrid simulations has been previously reported and implemented in the LICHEM code. 44,45 Here, we employ the same approach as developed by Kratz et al 44 The ECPs are of the form…”

Analytic Gradients for the Electrostatic Embedding QM/MM Model in Periodic Boundary Conditions Using Particle-Mesh Ewald Sums and Electrostatic Potential Fitted Charge Operators

“…Covalent bonds between the QM and MM regions create an unsaturated QM atom that fictitiously overpolarizes the QM density. Many methods exist to solve this problem. − The link atom (LA) remains the simplest and most widely used approach, − in which a QM auxiliary atom is placed between the QM and MM frontier atoms. According to Morokuma’s scheme, a LA is placed onto each QM and MM frontier ( f )­ in which r f , r f ,QM , and r f ,MM are, respectively, the positions of the LA, QM, and MM frontier atoms.…”

Impact of an Ionic Liquid Solution on Horseradish Peroxidase Activity

“…The MM environment was represented by using the polarizable AMOEBA force field. The pseudobond approach was utilized to handle covalent bonds spanning the QM/MM boundary. − Single-point calculations on all of the optimized critical points were performed at the ωB97X-D/6-311+G­(d,p)//AMOEBA level. Long-range electrostatic effects for all QM/MM calculations were accounted for via the QM/MM long-range electrostatic correction (QM/MM-LREC) , for QM coupled with the smooth particle mesh Ewald (sPME) for the MM utilizing a cutoff of 25 Å.…”