MCCE2: Improving protein pK_a calculations with extensive side chain rotamer sampling

Abstract

Multiconformation continuum electrostatics (MCCE) explores different conformational degrees of freedom in Monte Carlo calculations of protein residue and ligand pKas. Explicit changes in side chain conformations throughout a titration create a position dependent, heterogeneous dielectric response giving a more accurate picture of coupled ionization and position changes. The MCCE2 methods for choosing a group of input heavy atom and proton positions are described. The pKas calculated with different isosteric conformers, heavy atom rotamers and proton positions, with different degrees of optimization are tested against a curated group of 305 experimental pKas in 33 proteins. QUICK calculations, with rotation around Asn and Gln termini, sampling His tautomers and torsion minimum hydroxyls yield an RMSD of 1.34 with 84% of the errors being <1.5 pH units. FULL calculations adding heavy atom rotamers and side chain optimization yield an RMSD of 0.90 with 90% of the errors <1.5 pH unit. Good results are also found for pKas in the membrane protein bacteriorhodopsin. The inclusion of extra side chain positions distorts the dielectric boundary and also biases the calculated pKas by creating more neutral than ionized conformers. Methods for correcting these errors are introduced. Calculations are compared with multiple X-ray and NMR derived structures in 36 soluble proteins. Calculations with X-ray structures give significantly better pKas. Results with the default protein dielectric constant of 4 are as good as those using a value of 8.

L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH

“…MCCE2 56 was used to perform Monte Carlo simulations of amino acid side chain position and side chain and substrate protonation at equilibrium. The 2.3 Å structure of lactate dehydrogenase A (LDHA pdb identifier: 1I10 57 ) was used as input for all calculations (~60 computational hours at two Intel ® Xeon ™ 2.40 GHz Six Core CPU).…”

Mutation Analysis of Violaxanthin De-epoxidase Identifies Substrate-binding Sites and Residues Involved in Catalysis

“…Before performing the docking procedure, we calculated the residue protonation state, i.e. the pK a values of the lipocalin domain (VDE cd ), using MCCE version 2.4 (24) and DELPHI version 4 (25,26). MCCE default parameters were used, and at least three independent runs were performed.…”

Multi-haem cytochromes inShewanella oneidensisMR-1: structures, functions and opportunities

“…An early computational study used single-point continuum electrostatics calculations to compute the macroscopic redox potentials for the tetra-haem chain in the reaction centre of Rhodopseudomonas viridis and was able to qualitatively reproduce the experimental values [78]. An improvement in accuracy is offered by computational titration methods familiar from protein pKa (continuum electrostatics) calculations [79,80]. The continuum treatment allows for a very efficient estimation of the free energy of the many possible redox (and protonation) microstates (2 N for N redox sites), so that their Boltzmann occupation probability can be readily computed for a given electrode potential (and pH) using, for example, Monte Carlo sampling.…”