Multiscale simulations of proteins: from hybrid to full coarse grained representations.

LUCIANA CAPECE; ARIEL PETRUK; PAOLO CARLONI; MARCELO A. MARTI; DARIO A. ESTRIN

Cagliari

Simposio; 7th International Theoretical Biophysics Symposium; 2015

center for advanced studies, research and development in sardinia

p { margin-bottom: 0.1in; direction: ltr; line-height: 120%; text-align: left; widows: 2; orphans: 2; }p.western { font-family: "Times New Roman",serif; font-size: 12pt; }p.cjk { font-family: "宋体"; font-size: 12pt; }p.ctl { font-family: "Times New Roman"; font-size: 12pt; }In the recent years, many efforts have been done in order to obtain acoarse-grained model for proteins that provides an accuraterepresentation of the protein dynamics in the native state. [1] Inthis talk I will present two different approaches of native state CGsimulations. In the first approach we focus our attention in one region of theprotein (i.e. the active site) which is described with classicalatomistic force fields, while the remaining part of the system istreated with a simplified CG Go-model. This results in a hybridatomistic-coarse grained representation (MM/CG). We will show resultsof the MM/CG methodology applied to the study of the binding pocketof G-protein coupled receptors. GPCRs are involved in an enormousnumber of biochemical processes at the cell membrane. Human GPCRs areamong the most important targets of pharmaceutical intervention,constituting the target for ∼30%of clinically used drugs [2]. Thus, methods for investigating howligands bind to GPCRs are crucial not only for characterizingprocesses in cells but also for drug development In this work we haveextended a previously used hybrid molecular mechanics/coarse-grained(MM/CG) approach applied so far for enzymes developed at the group ofProf. Carloni [3] to GPCR/ligand complexes. The accuracy of thismethod for structural predictions was established by comparison withrecent atomistic molecular dynamics simulations on the human β2adrenergic receptor, a member of the GPCRs superfamily. The resultsobtained with the MM/CG methodology show a good agreement withprevious all-atom classical dynamics simulations, in particular inthe structural description of the ligand binding site. [4] Thisapproach was lately applied to a specific GPCR, the TAS2R38 bittertaste receptor. The method, through an extensive exploration of theconformational space in the binding pocket, allows the identificationof several residues important for agonist binding that would havebeen very difficult to capture from the standardbioinformatics/docking approach. [5]In the second approach, we apply a CG representation to the wholesystem in order to shed light on the effects of the dynamics of alarge region of the protein in a specific process. For this purpose,a more sophisticated CG model, which keeps information of theaminoacid sidechains is employed. We will show results concerningthe application of this scheme, developed originally by Voth et al.[6] to heme proteins. For this purpose, we parametrized the hemegroup following a similar procedure to the one followed originally todevelop the force field parameters for the standard aminoacids. Thisheme model was applied to different heme proteins, including themonomeric globins myoglobin (Mb) and neuroglobin (Ngb), andtetrameric human hemoglobin (Hb). Long-term equilibriumcoarse-grained molecular dynamics were run showing that thestructures are stable along the simulation and also retainqualitatively the flexibility patterns of the atomistic simulation.Inorder to further validate the heme model, we compared Mb and Ngb intheir behaviour toward endogenous heme hexacoordination. Experimentalinformation indicates that in the absence of a external ligand, Mbdisplays a pentacoordinated heme, while Ngb is hexacoordinated. InNgb, HisE7 (a histidine residue highly conserved in the family andpresent also in Mb) is coordinated to the iron in the distalposition, forming the 6c form. This is not observed in Mb. Previousatomistic molecular dynamics simulations allowed to characterizedynamically and structurally this transition and to obtain the freeenergy profiles for this transition. [7][8]The atomistic results indicate that this process is highly relatedwith the dynamics of the region that connects de E and the B helixes.We calculated the free energy profile for this process using the CGforce field in combination with the CG heme model. The results showthat the model is able to differentiate the behavior of Mb and Ngbtowards hexacoordination.