Multiscale Simulations of Biological Systems and Processes

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Project Summary The advance in understanding of the molecular basis of human health in the past few decades has been tremendous. However, we are far behind in terms of the conversion of the information about structures and sequence of proteins into the corresponding functions. The progress on this front can be greatly advanced by multiscale computer simulations that can treat different systems with increased level of complexity. At this stage we are ready to apply such methods to systems whose understanding are relevant to important medical problems, including studies of enzyme design, drug resistance and transport mechanism of protons and ions, thereby elucidating the basis of catalytic control, bioenergetics and energy transduction in living systems. Our proposed concerted directions are listed below. A.1 Control of Biochemical Processes by Enzymes: Many diseases can be controlled by developing drugs that block the action of enzymes in crucial biological pathways. The great advances in structural and biochemical studies have not yet led to a quantitative understanding of the energetics of enzymatic reactions. Further quantitative progress requires reliable tools for the structure-function correlation of enzymes. Our advances in this direction have led to the development of effective multiscale methods for simulating enzyme catalysis. At this stage it is important to exploit our advances and to progress simultaneously in the following directions: (a) Quantifying computer-aided enzyme design by: (i) reproducing the observed catalytic effects of key designer enzymes by the EVB and other multiscale approaches. (ii) Using our multiscale approaches in enzyme design projects, including changing the action of promiscuous enzymes, improving available designer enzymes and helping in the design of new enzymes. After exploring the predictive power of our approaches, we will use them in collaboration with research groups that are involved in enzyme design experiments. (b) Continuing to advance quantitative computational methods, including: (i) using our PD QM(ai)/MM in evaluating the ab initio free energy surfaces of enzymatic reactions; (ii) using the PD approach to automatically refine EVB surfaces for exploring long distance mutational effects and catalytic landscapes; and (iii) Quantifying the relationship between folding and stability. (c) Exploring the catalytic effect of directed evolution and determining its relationship to natural evolution. (d) Conducting studies of important classes of enzymatic reactions. (e) The relations of our finding to medical problems (including drug resistance) will be explored. A.2 Multiscale Modeling of the energetics and functions of complex biological systems: Proteins that guide the transport of electrons, protons and ions underpin basic functions of living cells. For example, proton pumps regulate the electrochemical gradient that drives the transport of molecules across membranes. Similarly, ion channels play a vital role in neural signal transduction and other functions. Mutations that disrupt the action of such systems are associated with many devastating diseases. Therefore these proteins present major targets for therapeutic intervention and play a central role in drug discovery efforts. Despite recent structural and biochemical progress in studies of proton pumps, ion channels and related systems, there are many cases where a quantitative structure-function correlation is still missing. Thus, it is crucial to develop, refine and apply quantitative structure-function correlations using computer simulation approaches. In the past we have made a major progress in converting structures to functions in systems that involve proton transport (PTR) and charge transport. This was done by developing microscopic and coarse grained (CG) approaches including multiscale approaches that allow us to explore very long time processes. Our multiscale models has placed us in a position where we can advance in the following directions: (a) Simulating the time evolution of PTR in proteins using realistic yet practical methods, where we can quantify the action of key proton- conducting systems and advance the following projects: (i) exploiting our initial progress and continue to explore the gating mechanism of the redox-coupled cytochrome c oxidase (CcO), putting more effort on well- defined channels where the activation barriers for PTR are known, including in ba3-type and related systems. (ii) Exploiting our recent breakthrough in modeling the conversion of pH gradients across the FO-ATPase system to a vectorial rotation and gaining a better understanding of the relevant proton paths. (iii) Exploring voltage activated PTR in Hv1. (iv) Continuing in our study of the PTR in bacteriorhodopsin (bR). (v) Exploiting our progress in realistic modeling of membrane potential to interpret the observed relationship between these potentials and the paths of the PT steps in CcO. (b) Exploiting our recent advances in modeling voltage activated ion channels to advance the following projects: (i) quantifying the interplay between the electrode potential and the protein/membrane landscape in voltage activation processes, (ii) reproducing the gating current and the subsequent ion current and selectivity. (iii) Validating our simulation methods. (c) Modeling the action of transporters by our multiscale approaches. (iv) Considering the relations between our finding to various diseases.