Proposta di ricerca:
Background, previous collaborations:
Intensive investigation of various processes occurring at interfaces between two bulk fluid phases
and at biological membranes came to the focus of scientific research in the past two decades. The
rapid and continuous increase of the available computing capacities now enables computer
simulation methods to meaningfully complement such experimental investigations. Recently our
group developed a new method that is suitable for identifying the exact location of the molecularly
rugged fluid interface, and analyzed a number of such interfaces in detail. Both groups performed
simulations of various biological lipid membranes, partly in collaboration with each other. The
calculation of the solvation free energy profile of small penetrants at such interfaces is a
computationally far more demanding task, and has not been performed yet with respect to the
aforementioned intrinsic interface. Our new method opens the possibility of such analyses.
Importance of the proposal:
In simulating fluid interfaces at an atomistic resolution, one has to face the problem that finding the
exact location of the interface is a difficult task. This problem is related to the fact that, on the
atomistic length scale, the liquid surface is corrugated by capillary waves. Neglecting this problem,
however, leads to a large systematic error of the calculated properties of the system. The recent
development of a novel method for identifying the truly interfacial molecules (ITIM) by our group
offers a way of circumventing this problem.
Solvation free energy profiles of small penetrants across interfaces represent the thermodynamic
driving force of their transport from one phase to the other. Knowing these profiles are thus of key
imprtance in various fields of chemistry from extraction to heterogeneous catalysys. The knowledge
of such profiles of anesthetics in lipid membranes is fundamental for understanding the molecular
mechanism of anesthesia. However, such calculations are scarcely reported in the literature, and
these studies are often conflicting with each other, in particular, in locating the preferred position of
such molecules.
Calculation of free energy profiles relative to the intrinsic interface has never been performed so far,
primarily due to the lack of suitable intrinsic surface analyzing methods. In this work we plan to
establish a protocol for such calculation, using the novel ITIM method, which would enable us to
address a number of important questions in heterogeneous solution chemistry.
Research scope:
One of the important goals of any intrinsic analysis is to calculate the profile of any physically
relevant quantity across the interface relative to the real, corrugated surface rather than to the Gibbs
dividing surface. The variation of the potential of mean force (PMF) acting on various components
represents a special case of these cross-surface profiles. The PMF is basically the profile of the
solvation free energy of the given component along the interface normal axis. Since PMF represents
the thermodynamic driving force of the transport of the particles from one phase to the other and
their partitioning between the two phases, reconstructing the exact profile is equally important
concerning the determination of the partition ratio of solutes, and for the description of their
transport from one phase to another. Needless to emphasize that the conventional, non-intrinsic way
of calculating the PMF is a huge source of systematic errors. Even this non-intrtinsic PMF
calculation is computationally rather costly, which is further exacerbated by the computing time of
even a fast intrinsic algorithm.
We will overcome these limitations, (i) developing novel and efficient algorithms for the calculation
of intrinsic PMF profiles that we will apply for (ii) determining of the solvation free energy profiles
of small ions and molecules at liquid/vapor and liquid/liquid interfaces, and (iii) calculating the
solvation free energy profile of various anesthetics in lipid membranes.
Advantages of the collaboration:
The scientific expertise of the two research groups is rather complementary from the point of view
of the proposed project. The Hungarian group, formed by chemists, has experience in simulating
fluid interfacial systems and in their intrinsic analysis. The ITIM method was also developed in this
group. The Italian group, formed by physicists, has expertise in developing and implementing fast
algorithms, which is of key importance in the success of this project. The collaboration of the two
teams will ensure that deep insight is gained into the physical-molecular background of chemical
processes to be studied. Both teams have experience in free energy calculation; however, the
methods used by the two teams are typically different. Both teams are experienced in lipid
membrane simulation. The two team members had a number of successful collaboration in the past
decade, which will ease the planned collaborative work.
Possible extension of the project:
The proposed project will form the core of a broader scientific collaboration in various respects.
Development of a method for intrinsic PMF calculation will foreseeingly involve the groups of
Prof. N. Cordeiro (University of Porto, Portugal) and Dr. M. Jorge (Stratchlyde University,
Glasgow, UK). The implementation and application of the energy representation method is planned
to be done also in collaboration with Prof. N. Matubayashi (University of Kyoto, Japan). Lipid
membrane simulations will be done together with the group of Prof. S. Picaud (University of
Franche-Comte, Besancon, France). The intrinsic PMF calculation methods will be applied for a
number of various penetrants and systems, which will involve an even broader network of
collaborators. These collaborations will form the basis of a subsequent application for forming a
research network, probably in the framework of Horizon2020.
Obiettivi:
(i) Methodological developments: Our goal is to modify "conventional" methods for free energy
calculation, like the PMF calculation or the newly developed Matubayashi method, so that the exact
position of the local interface (i.e. the intrinsic interface) is taken into account.
(ii) Free energy profiles of small ions/molecules at liquid/vapor and liquid/liquid interfaces:
We want to understand the micrsoscopical origin of the features observed using non-intrinsic
techniques in the free energy profiles of small molecules (Ar, CH4) and simple ions (Cl-, I-) crossing
liquid/vapor or liquid/liquid interfaces, in particular the air-water and aqueous-organic liquid-liquid
interfaces.
(iii) Free energy profiles of anesthetics in lipid membranes: We want to solve the problem of the
preferred location and extent of the membrane-crossing free energy barriers of anesthetics
(halothane, chloroform, diethyl ether and enflurane) in simple models for the human cell membrane
composed of a lipid bilayer in the biologically relevant liquid crystalline phase. The chosen
molecules show a variety in shape and polarity, and hence will eliminate the arbitratrriness inherent
in the particular choice of solely one type of anesthetic molecule. Our previous results showed that
at finite concentration in the gel phase of the membrane all of these molecules have a dual
preference along the membrane normal axis, and the solution of this problem in the biologically
pertinent phase is of particular relevance.