Coarse grained simulations of heme-proteins: reducing the cost while keeping the information

LUCIANA CAPECE; CLAUDIA RAMIREZ; LEANDRO E. LOMBARDI; ARIEL PETRUK; ADRIAN ROITBERG; DARIO A. ESTRIN; MARCELO A. MARTI

Salto

Congreso; Latin American Crosstalk in Biophysics and Physiology; 2015

Sociedad Uruguaya de Biofisica - Sociedad Argentina de Biofisica

p { margin-bottom: 0.1in; direction: ltr; line-height: 120%; text-align: left; widows: 2; orphans: 2; }p.western { font-size: 11pt; }p.cjk { font-size: 11pt; }p.ctl { font-family: "Times New Roman"; font-size: 11pt; }Inthe 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]Coarse grain (CG) models define particles by grouping togetherseveral atoms into one bead, reducing the number of particles by atleast an order of magnitude. This economy allows for longer scale(either temporal, spatial or both) simulations, allowing thecharacterization of complex processes in proteins. Inthis work, we applied a CG model developed originally by Voth et al.[2] 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 towards endogenous heme hexacoordination.Experimental information indicates that in the absence of an externalligand, Mb displays a pentacoordinated heme, while Ngb ishexacoordinated. The key differences between Mb and Ngb have beenstudied with atomistic molecular dynamics simulations. [3]CG simulations are able to capture the difference between Mb and Ngbin their behaviour towards hexacoordination. Wealso applied this model to describe the allosteric transition betweenthe R(Relaxed) and T(Tense) states in human hemoglobin, using acollective reaction coordinate. The CG model characterization is invery good agreement with the atomistic results, validating thisscheme for the treatment of allosteric processes in heme proteins.Finally,we present an algorithm to reconstruct (or backmap) the atomisticstructure from the coarse-grained representation. In this contextlow-cost CG simulations can be used to efficiently sample theconformational space, and CG structures can be later backmapped tothe atomistic representation, providing insight into processes inbiomolecules in the atomistic scale.