Conformational transitions

Department of Chemistry, M/C 111, University of Illinois at Chicago, P.O. Box 4348, Chicago IL 60680, USA.

Abstract

In biological molecules, one finds a large variety of conformational transitions which differ in their extent (from a single internal degree of freedom to a few thousands of atoms), their time scales, and their possible effects on biological function. The broad range of properties makes it difficult to study them in an automatic way. We initiated a program aimed at reaching better understanding of the dynamics of such transitions.

Different classes of transitions will be demonstrated through the following cases which we studied recently :

• (a)

  conformational transitions in tetrapeptides as models for the formation of secondary structure elements,

• (b)

  the B to Z transition in DNA,

• (c)

  protein fluctuations which open gates for ligand diffusion in myoglobin and leghemoglobin and

• (d)

  rearrangements of helices packing in myohemerythrin.

Several new computational methods developed by us to study the dynamics of the transitions will be presented.

The first method is the LES protocol (Locally Enhanced Sampling). In this approach a large number of copies of a small fragment of the system which is of particular interest are run in parallel. This is while including only one copy of the larger portion of the system (bath). The atomic detail picture of the "bath" is maintained while more efficient sampling of rare events compared to ordinary molecular dynamics is obtained. Applications to the diffusion of a small ligand (carbon monoxide) through protein matrices (myoglobin and leghemoglobin) will be demonstrated.

The second computational approach is evaluation of the reaction path. We describe a few of recently developed methodologies to calculate reaction coordinates in large systems and demonstrate specific applications to conformational transitions in tetrapeptides, to the B to Z transition in DNA and to carbon monoxide diffusion in leghemoglobin.

The third theoretical approach deals with the reduction in the number of degrees of freedom. We explore the possibility of studying protein dynamics on the level of secondary structure elements (helices). We show that the backbone fluctuations in myohemerythrin are dominated by rigid shifts of helices. We further extract potential of mean force for this type of motions. For most of the helix variables the mean force potential is close to harmonic, however, for certain orientation angles multiple minima were detected. The implication for the construction of empirical force field for helices’ dynamics will be discussed.