Conformation and Protonation Significantly Influence Methyl Dynamics Yielding Improved Rhodopsin Retinal Force Field

Abstract

Recent 2H nuclear magnetic resonance (NMR) studies on retinal in rhodopsin indicate a discrepancy in parameters for methyl rotation activation compared to previous molecular dynamics (MD) simulations [1,2]. Here we report ab initio quantum mechanical (QM) calculations of retinal potential energy surfaces that enable comparison to the results of 2H NMR relaxation measurements [3,4]. Rotational dynamics of the retinal ligand were assessed via C5-, C9-, and C13-methyl dihedral scans in retinal model compounds that correspond to 2H NMR data and allow us to validate the methyl dihedral contribution to the retinal force field [1,2]. We are able to accurately reproduce the retinal methyl rotational dynamics [3,4] by using larger retinal fragments and a higher level of theory (MP2/cc-pVDZ). Distinct behaviors for each retinal methyl group emerge in agreement with experiment [3,4]. Few differences exist between the QM and original MD calculations for the C5-methyl group. However, the C9-methyl shows a markedly lower dihedral energy barrier compared to previous models, due to intra-retinal steric affects. Moreover, the C13-methyl rotational barrier is lowered by two effects: (1) cis to trans isomerization increases hyperconjugation influences along the polyene chain, and (2) the protonated Schiff base charge is delocalized proximal to the polyene chain and methyl group. Accounting for these effects leads to development of new methyl dihedral parameters for the retinal force field. Our results are directly applicable to rhodopsin MD simulations and potentially enable the simulation of coupling of local dynamics to large-scale motions in rhodopsin activation. [1] P.-W. Lau et al. (2007) JMB 372, 906-917. [2] K. Martínez-Mayorga et al. (2006) JACS 128, 16502-16503. [3] M.F. Brown et al. (2010) BBA 1798, 177-193. [4] A.V. Struts et al. Nat. Struct. Mol. Biol. (in press).